Regulation of TNF-Induced Osteoclast Differentiation

Yao, Zhenqiang; Getting, Stephen J.; Locke, Ian C.

doi:10.3390/cells11010132

Cited by 280Bone Metabolism and DiseasesRheumatoid Arthritis Research and TherapiesOsteomyelitis and Bone Disorders Research

Regulation of TNF-Induced Osteoclast Differentiation

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Yao, Zhenqiang, Getting, Stephen J., Locke, Ian C.·2021·Cells

DOI 10.3390/cells11010132PMC PMC8750957

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Abstract

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

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Different concentrations of TGF-β have different effects on the RANKL/OPG ratio and osteoclast differentiation: low concentrations increase stimulation of osteoclast differentiation, while high concentrations have the opposite effect.
“Different concentrations of TGF-β have different effects on the RANKL/OPG ratio and ultimately on osteoclast differentiation (low concentrations of TGF-β increase the stimulation of osteoclast differentiation, while high concentrations of TGF-β have the opposite effect) [98, 99].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [99]

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“An activated OC is characterized by cytoskeletal reorganization, the formation of sealing zones, and a specialized cell membrane, called a ruffled border, which opposes the surface of the bone tissue, allowing the secretion of acids and lysosomal enzymes onto the surface of bone to be resorbed [42,43].”
Background
Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases
Guise, T. A., Mohammad, K. S., Clines, G. A., Stebbins, E. G., Wong, D. H., Higgins, L. S., Vessella, R. L., Corey, E., Padalecki, S. S., Suva, L. J., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1007 · Cited by 539 · cited 1× · see citing works
“Imbalance of bone remodeling (increased OC bone resorption and/or decreased OB bone formation) results in bone loss, contributing to common diseases affecting adult bone, including osteoporosis [1–3], rheumatoid arthritis (RA), [4,5], bone metastatic cancer [6,7], aseptic loosening of arthroplasty [8], and periodontit…”
Background
Osteoclasts are essential for TNF-α–mediated joint destruction
Redlich, K., Hayer, S., Ricci, R., David, J., Tohidast-Akrad, M., Kollias, G. A., Steiner, G. E., Smolen, J. S., Wagner, E. F., & Schett, G. A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15582 · Cited by 534 · see citing works
Adverse effects of bisphosphonates: Implications for osteoporosis management
Kennel, K. A., & Drake, M. T. (2009) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(11)60752-0 · Cited by 496 · cited 1× · see citing works
“In summary, the efficacy of current anti-resorptive and anabolic agents in treating osteoporosis and other bone diseases is limited, and their side effects have resulted in poor patient compliance, with many patients going untreated [40,41].”
Background
Osteoclasts are essential for TNF-α-mediated joint destruction.
Redlich, K., Hayer, S., Ricci, R., David, J.-P., Tohidast-Akrad, M., Kollias, G., Steiner, G., Smolen, J. S., Wagner, E. F., & Schett, G. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215582 · Cited by 474 · see citing works
Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update
Shoback, D., Rosen, C. J., Black, D. M., Cheung, A. M., Murad, M. H., & Eastell, R. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa048 · Cited by 452 · cited 1× · see citing works
“Thus, romosozumab is only recommended for treatment of severe osteoporosis for up to 1 year [39].”
Background
Successful Bone-Marrow Transplantation for Infantile Malignant Osteopetrosis
Coccia, P. F., Krivit, W. A., Červenka, J., Clawson, C., Kersey, J. H., Kim, T. H., Nesbit, M. E., Ramsay, N. K. C., Warkentin, P. I., Teitelbaum, S. L., et al. (1980) · New England Journal of Medicine · doi:10.1056/nejm198003273021301 · Cited by 450 · cited 1× · see citing works
“However, some published data indicates that serum levels of RANKL are reduced [81,82] while OPG is increased [55,83,84] with aging and in postmenopausal osteoporotic women.”
Background
Osteoprotegerin Deficiency and Juvenile Paget's Disease
Whyte, M. P., Obrecht, S. E., Finnegan, P. M., Jones, J. L., Podgornik, M. N., McAlister, W. H., & Mumm, S. R. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa013096 · Cited by 446 · see citing works
The role of NFAT in osteoclast formation
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“NFATc1 is the master transcription factor regulating OC differentiation [73,74], and thus, over-expression of NFATc1 results in the terminal differentiation and fusion of OCPs without adding RANKL [73,74], and can rescue the defect of RANKL- and TNF-induced OC formation caused by the deletion of NF-κB p50/p52 or c-Fos…”
Background
P <scp>ost-translational</scp> M <scp>odifications of</scp> SIBLING P <scp>roteins and</scp> T <scp>heir</scp> R <scp>oles in</scp> O <scp>steogenesis and</scp> D <scp>entinogenesis</scp>
Qin, C., Baba, O., & Butler, W. T. (2004) · Critical Reviews in Oral Biology & Medicine · doi:10.1177/154411130401500302 · Cited by 439 · see citing works
Dimorphic effects of Notch signaling in bone homeostasis
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Self-citation
NF-κB p50 and p52 Regulate Receptor Activator of NF-κB Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1*
Yamashita, T., Yao, Z., Li, F., Zhang, Q., Badell, I., Schwarz, E., Takeshita, S., Wagner, E., Noda, M., Matsuo, K., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610701200 · Cited by 412 · cited 10× · see citing works
“TNFα alone weakly induces OC differentiation that is independent of RANKL signaling [72].”
BackgroundInfluentialSelf-citation
Antifracture Efficacy of Antiresorptive Agents Are Related to Changes in Bone Density
Wasnich, R. D., & Miller, P. D. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.1.6267 · Cited by 402 · cited 1× · see citing works
“The widely prescribed anti-resorptive drugs, bisphosphonates [11], effectively increase bone mass, and reduce the rate of osteoporotic fracture by 50% [12].”
Background
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
Smith, A. M., Rahman, F. Z., Hayee, B., Graham, S. J., Marks, D. J., Sewell, G. W., Palmer, C. D., Wilde, J. I., Foxwell, B. M. J., Gloger, I., et al. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20091233 · Cited by 399 · see citing works
Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis
Taylor, P., & Feldmann, M. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.181 · Cited by 391 · see citing works
Mechanisms of cancer metastasis to the bone
Yin, J. J., Pollock, C. B., & Kelly, K. (2005) · Cell Research · doi:10.1038/sj.cr.7290266 · Cited by 378 · cited 1× · see citing works
“Imbalance of bone remodeling (increased OC bone resorption and/or decreased OB bone formation) results in bone loss, contributing to common diseases affecting adult bone, including osteoporosis [1–3], rheumatoid arthritis (RA), [4,5], bone metastatic cancer [6,7], aseptic loosening of arthroplasty [8], and periodontit…”
Background
Interleukin-18 (Interferon-γ–inducing Factor) Is Produced by Osteoblasts and Acts Via Granulocyte/Macrophage Colony-stimulating Factor and Not Via Interferon-γ to Inhibit Osteoclast Formation
Udagawa, N., Horwood, N. J., Elliott, J., Mackay, A., Owens, J., Okamura, H., Kurimoto, M., Chambers, T. J., Martin, T. J., & Gillespie, M. T. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.6.1005 · Cited by 378 · see citing works
Osteoclast differentiation independent of the TRANCE–RANK–TRAF6 axis
Kim, N., Kadono, Y., Takami, M., Lee, J., Lee, S.-H., Okada, F., Kim, J. H., Kobayashi, T., Odgren, P. R., Nakano, H., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050978 · Cited by 371 · cited 7× · see citing works
“TGFβ1 Enhances TNF-induced OC formation independent of RANKL, RANK, and TRAF6 [87,93].”
Influential
Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management
Kennel, K. A., & Drake, M. T. (2009) · Mayo Clinic Proceedings · doi:10.4065/84.7.632 · Cited by 369 · see citing works
Cancellous bone remodeling in type i (postmenopausal) osteoporosis: Quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels
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Effects of Interleukin-1 on Bone Turnover in Normal Mice*
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Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor.
Kodama, H., Yamasaki, A., Nose, M., Niida, S., Ohgame, Y., Abe, M., Kumegawa, M., & Suda, T. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.1.269 · Cited by 353 · see citing works
Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis
Zhao, B., Takami, M., Yamada, A., Wang, X., Koga, T., Hu, X., Tamura, T., Ozato, K., Choi, Y., Ivashkiv, L. B., et al. (2009) · Nature Medicine · doi:10.1038/nm.2007 · Cited by 313 · cited 6× · see citing works
“Interestingly, over-expression of NFATc1, the down-stream transcriptional factor of c-Fos during OC differentiation [75], results in OC formation from both WT and NF-κB p50/p52 double knockout OCPs without the addition of RANKL or TNFα, and significantly enhances both RANKL and TNFα induction of OC formation from both…”
BackgroundInfluential
Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis
Baraliakos, X., Haibel, H., Listing, J., Sieper, J., & Braun, J. (2013) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2012-202698 · Cited by 305 · see citing works
Tumor necrosis factor α-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin.
Redlich, K., Hayer, S., Maier, A., Dunstan, C. R., Tohidast‐Akrad, M., Lang, S., Türk, B., Pietschmann, P., Woloszczuk, W., Haralambous, S., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10097 · Cited by 285 · cited 3× · see citing works
“In addition, TNF-Tg mice generated to have a deficiency of RANKL still developed synovial inflammation, although joint destruction was blocked due to OC defect [4,5].”
Background
Activation of the bone-derived latent TGF beta complex by isolated osteoclasts
Oreffo, R. O. C., Mundy, G. R., Seyedin, S. M., & Bonewald, L. F. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)92795-2 · Cited by 285 · see citing works
Bifurcation of osteoclasts and dendritic cells from common progenitors
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Transforming Growth Factor β Affects Osteoclast Differentiation via Direct and Indirect Actions
Quinn, J. M. W., Itoh, K., Udagawa, N., Häusler, K., Yasuda, H., Shima, N., Mizuno, A., Higashio, K., Takahashi, N., Suda, T., et al. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.10.1787 · Cited by 278 · see citing works
Essential role of macrophage colony-stimulating factor in the osteoclast differentiation supported by stromal cells.
Kodama, H., Nose, M., Niida, S., & Yamasaki, A. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.5.1291 · Cited by 277 · see citing works
The IκB Function of NF-κB2 p100 Controls Stimulated Osteoclastogenesis
Novack, D., Yin, L., Hagen-Stapleton, A., Schreiber, R. D., Goeddel, D., Ross, F. P., & Teitelbaum, S. L. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20030116 · Cited by 275 · see citing works
Osteonecrosis of the Jaw in a Patient on Denosumab
Aghaloo, T. L., Felsenfeld, A. L., & Tetradis, S. (2010) · Journal of Oral and Maxillofacial Surgery · doi:10.1016/j.joms.2009.10.010 · Cited by 274 · cited 1× · see citing works
“Another anti-resorptive agent, denosumab (RANKL inhibitor), can also result in bone necrosis [23].”
Background
Rescue of osteoclast function by transgenic expression of kinase-deficient Src insrc−/− mutant micePreprint
Schwartzberg, P. L., Xing, L., Hoffmann, O., Lowell, C. A., Garrett, L. J., Boyce, B. F., & Varmus, H. E. (1997) · Genes & Development · doi:10.1101/gad.11.21.2835 · Cited by 268 · cited 1× · see citing works
“Being deficient in sealing zone and ruffled border, as a result of defect of src kinase [44] or αv/β3 integrin [45], for example, incur OCs losing their resorptive function in mice.”
Background
TRAF6 Is a Critical Factor for Dendritic Cell Maturation and Development
Kobayashi, T., Walsh, P. T., Walsh, M. C., Speirs, K. M., Chiffoleau, E., King, C. G., Hancock, W. W., Caamaño, J., Hunter, C. A., Scott, P., et al. (2003) · Immunity · doi:10.1016/s1074-7613(03)00230-9 · Cited by 267 · see citing works
Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9
Zając, E., Schweighofer, B., Kupriyanova, T. A., Juncker‐Jensen, A., Minder, P., Quigley, J. P., & Deryugina, E. I. (2013) · Blood · doi:10.1182/blood-2013-05-501494 · Cited by 261 · see citing works
TNF.ALPHA. and pathologic bone resorption
Boyce, B., Li, P., Yao, Z., Zhang, Q., Badell, I. R., Schwarz, E. M., O’Keefe, R. J., & Xing, L. (2005) · The Keio Journal of Medicine · doi:10.2302/kjm.54.127 · Cited by 260 · see citing works
Self-citation
Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis
Cosman, F., Nieves, J. W., & Dempster, D. W. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3051 · Cited by 253 · cited 2× · see citing works
“However, when patients established on potent bisphosphonates and denosumab are switched to teriparatide, the hip BMD declines below baseline for at least 12 and 24 months, respectively, after the switch to this anabolic agent [33].”
Background
IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro
Horwood, N. J., Elliott, J., Martin, T. J., & Gillespie, M. T. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.4915 · Cited by 248 · see citing works
NOTCH1 Regulates Osteoclastogenesis Directly in Osteoclast Precursors and Indirectly via Osteoblast Lineage Cells
Bai, S., Kopan, R., Zou, W., Hilton, M. J., Ong, C., Long, F., Ross, F. P., & Teitelbaum, S. L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707000200 · Cited by 236 · see citing works
Osteoclast precursors, RANKL/RANK, and immunology
Xing, L., Schwarz, E. M., & Boyce, B. F. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00336.x · Cited by 234 · see citing works
Osteoblasts in osteoporosis: Past, emerging, and future anabolic targets
Marie, P. J., & Kassem, M. (2011) · European Journal of Endocrinology · doi:10.1530/eje-11-0132 · Cited by 234 · cited 1× · see citing works
“In postmenopausal osteoporosis, bone resorption is increased, associated with a coupled increase in bone formation [1–3], but bone formation relative to bone resorption is reduced [10], resulting in the accelerated bone turnover, and, finally, bone loss.”
Background
Investigation of cell lineage in bone using a chimaera of chick and quail embryonic tissue
Kahn, A. J., & Simmons, D. J. (1975) · Nature · doi:10.1038/258325a0 · Cited by 231 · see citing works
Secular trends in hip fracture incidence and recurrence
Melton, L. J., Kearns, A. E., Atkinson, E. J., Bolander, M. E., Achenbach, S. J., Huddleston, J. M., Therneau, T. M., & Leibson, C. L. (2008) · Osteoporosis International · doi:10.1007/s00198-008-0742-8 · Cited by 220 · cited 1× · see citing works
“44% per year in men in the Rochester area, US [14].”
Background
Dual Modulation of Osteoclast Differentiation by Lipopolysaccharide
Zou, W., & Bar-Shavit, Z. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.7.1211 · Cited by 219 · see citing works
NF‐κB regulation: lessons from structures
Ghosh, G., Wang, V. Y., Huang, D., & Fusco, A. J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01097.x · Cited by 209 · see citing works
Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release
Sierra‐Filardi, E., Vega, M. A., Sánchez‐Mateos, P., Corbí, A. L., & Puig‐Kröger, A. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.05.020 · Cited by 204 · see citing works
Interleukin-4 Reversibly Inhibits Osteoclastogenesis via Inhibition of NF-κB and Mitogen-activated Protein Kinase Signaling
Wei, S., Wang, M. W.-H., Teitelbaum, S. L., & Ross, F. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m104957200 · Cited by 202 · see citing works
Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density
Lodder, M. C., de Jong, Z., Kostense, P. J., Molenaar, E. T. H., Staal, K., Voskuyl, A. E., Hazes, J. M. W., Dijkmans, B. A. C., & Lems, W. F. (2004) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2003.016253 · Cited by 202 · see citing works
Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review
Anastasilakis, A. D., Makras, P., Yavropoulou, M. P., Tabacco, G., Naciu, A. M., & Palermo, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10010152 · Cited by 202 · cited 1× · see citing works
“One special concern for denosumab is that its discontinuation is associated with a subsequent profound increase of bone turnover above pre-treatment values due to a substantial increase in OC number and activity, resulting in a risk of multiple vertebral fractures [24,25].”
Background
Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus
Evans, K. E., & Fox, S. W. (2007) · BMC Cell Biology · doi:10.1186/1471-2121-8-4 · Cited by 198 · see citing works
Origin of osteoclasts from mononuclear leucocytes in regenerating newt limbs
Fischman, D. A., & Hay, E. D. (1962) · The Anatomical Record · doi:10.1002/ar.1091430402 · Cited by 195 · see citing works
Depletion of Plasmacytoid Dendritic Cells Inhibits Tumor Growth and Prevents Bone Metastasis of Breast Cancer Cells
Sawant, A., Hensel, J. A., Chanda, D., Harris, B. A., Siegal, G. P., Maheshwari, A., & Ponnazhagan, S. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101855 · Cited by 191 · cited 1× · see citing works
“Thus, depletion of plasmacytoid dendritic cells inhibits osteolysis caused by breast cancer bone metastasis [63].”
Background
Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications.
Goldring, S. R., & Gravallese, E. M. (2000) · Arthritis Research · doi:10.1186/ar67 · Cited by 190 · see citing works
Roles of stromal cell RANKL, OPG, and M‐CSF expression in biphasic TGF‐β regulation of osteoclast differentiation
Karst, M., Gorny, G., Galvin, R. J. S., & Oursler, M. J. (2004) · Journal of Cellular Physiology · doi:10.1002/jcp.20036 · Cited by 184 · see citing works
TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J
Zhao, B., Grimes, S. N., Li, S., Hu, X., & Ivashkiv, L. B. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20111566 · Cited by 182 · cited 9× · see citing works
“* RBP-j Suppresses NFATc1 to inhibit OC formation [95].”
BackgroundInfluential
IL-10, But Not IL-4, Suppresses Infection-Stimulated Bone Resorption In Vivo
Sasaki, H., Hou, L. A., Belani, A., Wang, C., Uchiyama, T., Müller, R., & Stashenko, P. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.7.3626 · Cited by 180 · see citing works
Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment
Chavassieux, P., Chapurlat, R. D., Portero-Muzy, N., Roux, J.-P., Garcia, P., Brown, J. P., Libanati, C. R., Boyce, R. W., Wang, A., & Grauer, A. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3735 · Cited by 179 · cited 1× · see citing works
“The newly approved romosozumab (a sclerostin monoclonal Ab) has a dual effect to increase bone formation early (and transiently), while inhibiting bone resorption persistently to treat osteoporosis [38].”
Background
The Association of Notch2 and NF-κB Accelerates RANKL-Induced Osteoclastogenesis
Fukushima, H., Nakao, A., Okamoto, F., Shin, M., Kajiya, H., Sakano, S., Bigas, A., Jimi, E., & Okabe, K. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00299-08 · Cited by 178 · see citing works
Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw
Sedghizadeh, P. P., Stanley, K., Caligiuri, M., Hofkes, S., Lowry, B., & Shuler, C. F. (2009) · The Journal of the American Dental Association · doi:10.14219/jada.archive.2009.0019 · Cited by 174 · cited 2× · see citing works
“Of concern is that bisphosphonates can result in atypical femoral fractures [16,17], hypocalcemia [18], and osteonecrosis of jaw bone [19,20] in a small number of patients.”
Background
The anabolic effect of human PTH (1–34) on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate—is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodeling system?
Delmas, P. D., Vergnaud, P., ARLOT, M. E., Pastoureau, P., Meunier, P. J., & Nilssen, M. H. L. (1995) · Bone · doi:10.1016/8756-3282(95)00113-r · Cited by 171 · cited 1× · see citing works
“However, the effect of anabolic agents to increase bone mass is transient, and discontinuing these agents abruptly decreases bone mineral density (BMD) [29] due to increased bone resorption [30].”
Background
Inhibition of Hormone and Cytokine-stimulated Osteoclastogenesis and Bone Resorption by Interleukin-4 and Interleukin-13 Is Associated with Increased Osteoprotegerin and Decreased RANKL and RANK in a STAT6-dependent Pathway
Palmqvist, P., Lundberg, P., Persson, E., Johansson, A., Lundgren, I., Lie, A., Conaway, H. H., & Lerner, U. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m510160200 · Cited by 167 · see citing works
Rescue of TRAF3-null mice by p100 NF-κB deficiency
He, J. Q., Zarnegar, B. J., Oganesyan, G., Saha, S. K., Yamazaki, S., Doyle, S. E., Dempsey, P. W., & Cheng, G. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061166 · Cited by 166 · see citing works
Osteoporosis induced in mice by overproduction of interleukin 4.
Lewis, D. B., Liggitt, H. D., Effmann, E. L., Motley, S. T., Teitelbaum, S. L., Jepsen, K. J., Goldstein, S. A., Bonadio, J. F., Carpenter, J., & Perlmutter, R. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11618 · Cited by 165 · see citing works
Interferon-Regulatory Factors Determine Macrophage Phenotype Polarization
Günthner, R., & Anders, H. (2013) · Mediators of Inflammation · doi:10.1155/2013/731023 · Cited by 164 · see citing works
Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation
Xiu, Y., Xu, H., Zhao, C., Li, J., Morita, Y., Yao, Z., Xing, L., & Boyce, B. F. (2014) · Journal of Clinical Investigation · doi:10.1172/jci66947 · Cited by 164 · cited 6× · see citing works
“Importantly, treatment of OCPs with TRAF3 siRNA prevents TNFα- induced NF-κB2 p100 accumulation and inhibition of osteoclastogenesis [91], whereas over-expression of TRAF3 inhibits RANKL-induced OC formation directly [92].”
BackgroundInfluentialSelf-citation
NF-kappaB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism.
Yao, Z., Xing, L., & Boyce, B. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38716 · Cited by 160 · cited 7× · see citing works
“NF-κB2 p100 Inhibits OC formation [91].”
BackgroundMethodInfluentialSelf-citation
Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance
Lloyd, A. A., Gludovatz, B., Riedel, C., Luengo, E. A., Saiyed, R., Marty, E., Lorich, D. G., Lane, J. M., Ritchie, R. O., Busse, B., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704460114 · Cited by 158 · cited 1× · see citing works
“Of concern is that bisphosphonates can result in atypical femoral fractures [16,17], hypocalcemia [18], and osteonecrosis of jaw bone [19,20] in a small number of patients.”
Background
Do RANKL inhibitors (denosumab) affect inflammation and immunity?
Ferrari, S., & Ferrari, S. (2010) · Osteoporosis International · doi:10.1007/s00198-010-1326-y · Cited by 157 · cited 1× · see citing works
“Clinical trials indicate that RANKL inhibitor, denosumab, did not alter RA disease activity [27,85], and did not suppress joint space narrowing, although it caused sustained suppression of bone turnover in RA patients [27].”
Background
Glanzmann thrombasthenia: genetic basis and clinical correlates
Botero, J. P., Lee, K., Branchford, B. R., Bray, P. F., Freson, K., Lambert, M. P., Luo, M., Mohan, S., Ross, J. E., Bergmeier, W., et al. (2020) · Haematologica · doi:10.3324/haematol.2018.214239 · Cited by 152 · cited 1× · see citing works
“Similarly, there is no report showing that an αv/β3 integrin genetic mutation causes abnormal OC function and osteopetrosis in humans, although defects in αIIb/β3 integrin causes Glanzmann thrombasthenia with bleeding in humans [48].”
Background
Osteoclasts; culprits in inflammatory osteolysis
Teitelbaum, S. (2005) · Arthritis Research & Therapy · doi:10.1186/ar1857 · Cited by 150 · see citing works
Managing Macrophages in Rheumatoid Arthritis by Reform or Removal
Li, ., Hsu, H., & Mountz, J. D. (2012) · Current Rheumatology Reports · doi:10.1007/s11926-012-0272-4 · Cited by 149 · see citing works
Notch and the Skeleton
Zanotti, S., & CANALIS, E. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01285-09 · Cited by 147 · see citing works
RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation
Vaira, S., Johnson, T., Hirbe, A. C., Alhawagri, M., Anwisye, I., Sammut, B., O'Neal, J., Zou, W., Weilbaecher, K. N., Faccio, R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708576105 · Cited by 141 · see citing works
Safety of osteoanabolic therapy: A decade of experience
Capriani, C., Irani, D., & Bilezikian, J. P. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1800 · Cited by 141 · see citing works
Origin of Osteoclasts from the Fusion of Phagocytes
Jee, W. S. S., & NOLAN, P. D. (1963) · Nature · doi:10.1038/200225a0 · Cited by 140 · see citing works
Stimulation of Osteoprotegerin (OPG) Gene Expression by Transforming Growth Factor-β (TGF-β)
Thirunavukkarasu, K., Miles, R. R., Halladay, D., Yang, X., Galvin, R. J. S., Chandrasekhar, S., Martin, T. J., & Onyia, J. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104319200 · Cited by 138 · see citing works
RANKL Stimulates Inducible Nitric-oxide Synthase Expression and Nitric Oxide Production in Developing Osteoclasts
Zheng, H. X., Yu, X., Collin‐Osdoby, P., & Osdoby, P. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513225200 · Cited by 137 · see citing works
M2 Polarization of Human Macrophages Favors Survival of the Intracellular Pathogen Chlamydia pneumoniae
Buchacher, T., Ohradanova‐Repic, A., Stockinger, H. S. J., Fischer, M. B., & Weber, V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143593 · Cited by 136 · see citing works
Formation and function of the ruffled border in osteoclasts
Stenbeck, G. (2002) · Seminars in Cell and Developmental Biology · doi:10.1016/s1084952102000587 · Cited by 133 · cited 1× · see citing works
“An activated OC is characterized by cytoskeletal reorganization, the formation of sealing zones, and a specialized cell membrane, called a ruffled border, which opposes the surface of the bone tissue, allowing the secretion of acids and lysosomal enzymes onto the surface of bone to be resorbed [42,43].”
Background
Instructive cytokine signals in dendritic cell lineage commitment
Schmid, M., Kingston, D., Boddupalli, S. S., & Manz, M. G. (2010) · Immunological Reviews · doi:10.1111/j.0105-2896.2009.00877.x · Cited by 133 · see citing works
Cutting Edge: The IκB Kinase (IKK) Inhibitor, NEMO-Binding Domain Peptide, Blocks Inflammatory Injury in Murine Colitis
Shibata, W., Maeda, S., Hikiba, Y., Yanai, A., Ohmae, T., Sakamoto, K., Nakagawa, H., Ogura, K., & Omata, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.2681 · Cited by 130 · see citing works
GM-CSF Regulates Fusion of Mononuclear Osteoclasts into Bone-Resorbing Osteoclasts by Activating the Ras/ERK Pathway
Lee, M. S., Kim, H. S., Yeon, J., Choi, S., Chun, C. H., Kwak, H. B., & Oh, J. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804314 · Cited by 125 · cited 1× · see citing works
“However, as a DC stimulating factor, granulocyte macrophage-colony stimulating factor (GM-CSF), strongly inhibits OC formation [64], although it stimulates the fusion of mononuclear OC precursors into bone-resorbing OCs by activating the Ras/ERK pathway [65].”
Background
Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells
Yamada, T., Yamazaki, H., Yamane, T., Yoshino, M., Okuyama, H., Tsuneto, M., Kurino, T., Hayashi, S., & Sakano, S. (2003) · Blood · doi:10.1182/blood-2002-06-1740 · Cited by 124 · see citing works
IL-10 Suppresses Calcium-Mediated Costimulation of Receptor Activator NF-κB Signaling during Human Osteoclast Differentiation by Inhibiting TREM-2 Expression
Park‐Min, K., Ji, J.-D., Antoniv, T. T., Reid, A. C., Silver, R. B., Humphrey, M. B., Nakamura, M. C., & Ivashkiv, L. B. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804165 · Cited by 122 · see citing works
Interleukin-10 inhibits RANKL-mediated expression of NFATc1 in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells
Mohamed, S. G.-K., Sugiyama, E., Shinoda, K., Taki, H., Hounoki, H., Abdel-Aziz, H. O., Maruyama, M., Kobayashi, M., Ogawa, H., & Miyahara, T. (2007) · Bone · doi:10.1016/j.bone.2007.05.016 · Cited by 120 · see citing works
Endogenous Production of TGF-β Is Essential for Osteoclastogenesis Induced by a Combination of Receptor Activator of NF-κB Ligand and Macrophage-Colony- Stimulating Factor
Kaneda, T., Nojima, T., Nakagawa, M., Ogasawara, A., Kaneko, H., Sato, T., Mano, H., Kumegawa, M., & Hakeda, Y. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.8.4254 · Cited by 119 · see citing works
Transforming growth factor-β induces osteoclast formation in the absence of RANKL
Itonaga, I., Sabokbar, A., Sun, S. G., Kudo, O., Danks, L., Ferguson, D. J. P., Fujikawa, Y., & Athanasou, N. A. (2003) · Bone · doi:10.1016/j.bone.2003.08.008 · Cited by 119 · see citing works
TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation
Kullberg, M. C., Hay, V., Cheever, A. W., Mamura, M., Sher, A., Letterio, J. J., Shevach, E. M., & Piccirillo, C. A. (2005) · European Journal of Immunology · doi:10.1002/eji.200526106 · Cited by 118 · see citing works
National Trends in Osteoporosis Visits and Osteoporosis Treatment, 1988-2003
Stafford, R. S., Drieling, R. L., & Hersh, A. L. (2004) · Archives of Internal Medicine · doi:10.1001/archinte.164.14.1525 · Cited by 117 · see citing works
Regulation of RANKL‐induced osteoclastogenesis by TGF‐β through molecular interaction between Smad3 and Traf6
Yasui, T., Kadono, Y., Nakamura, M., Oshima, Y., Matsumoto, T., Masuda, H., Hirose, J., Omata, Y., Yasuda, H., Imamura, T., et al. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.357 · Cited by 114 · see citing works
Murine dendritic cell transdifferentiation into osteoclasts is differentially regulated by innate and adaptive cytokines
Speziani, C., Rivollier, A., Gallois, A., Coury, F., Mazzorana, M., Azocar, O., Flacher, M., Bella, C., Tebib, J. G., Jurdic, P., et al. (2007) · European Journal of Immunology · doi:10.1002/eji.200636534 · Cited by 113 · cited 1× · see citing works
“DCs can transdifferentiate toward functional OCs upon inflammatory conditions [62].”
Background
Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: The Denosumab and Teriparatide Follow-up study (DATA-Follow-up)
Leder, B. Z., Tsai, J. N., Jiang, L. A., & Lee, H. (2017) · Bone · doi:10.1016/j.bone.2017.03.006 · Cited by 112 · cited 7× · see citing works
“Lumbar and femoral neck BMD are even reduced after short-term anti-TNF therapy in patients with RA [147].”
BackgroundInfluential
Osteoclast Precursor Interaction with Bone Matrix Induces Osteoclast Formation Directly by an Interleukin-1-mediated Autocrine Mechanism
Yao, Z., Xing, L., Qin, C., Schwarz, E. M., & Boyce, B. F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706415200 · Cited by 109 · cited 9× · see citing works
“The role of NF-κB in OC differentiation was discovered in the late 1990s when NFκB1−/− mice were crossed with NF-κB2−/− mice to generate NF-κB1/2 double knockout (dKO) mice that developed severe osteopetrosis due to an OC defect [121,122].”
BackgroundInfluentialSelf-citation
Interleukin‐4 inhibition of osteoclast differentiation is stronger than that of interleukin‐13 and they are equivalent for induction of osteoprotegerin production from osteoblasts
Yamada, A., Takami, M., Kawawa, T., Yasuhara, R., Zhao, B., Mochizuki, A., Miyamoto, Y., Eto, T., Yasuda, H., Nakamichi, Y., et al. (2007) · Immunology · doi:10.1111/j.1365-2567.2006.02538.x · Cited by 106 · see citing works
RANKL-dependent and RANKL-independent mechanisms of macrophage-osteoclast differentiation in breast cancer
Lau, Y. S., Danks, L., Sun, S. G., Fox, S. B., Sabokbar, A., Harris, A. L., & Athanasou, N. A. (2006) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9438-y · Cited by 101 · see citing works
Specificity of TRAF3 in Its Negative Regulation of the Noncanonical NF-κB Pathway
He, J. Q., Saha, S. K., Kang, J. R., Zarnegar, B. J., & Cheng, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m610271200 · Cited by 101 · see citing works
Bisphosphonate Associated Osteonecrosis of the Jaw: An Update on Pathophysiology, Risk Factors, and Treatment
Rasmusson, L., & Abtahi, J. (2014) · International Journal of Dentistry · doi:10.1155/2014/471035 · Cited by 95 · cited 1× · see citing works
“In summary, the efficacy of current anti-resorptive and anabolic agents in treating osteoporosis and other bone diseases is limited, and their side effects have resulted in poor patient compliance, with many patients going untreated [40,41].”
Background
Current insights into the role of transforming growth factor-β in bone resorption
Fox, S. W., & Lovibond, A. C. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.09.008 · Cited by 90 · see citing works
Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling
AlQranei, M. S., Senbanjo, L. T., Aljohani, H., Hamza, T., & Chellaiah, M. (2021) · BMC Immunology · doi:10.1186/s12865-021-00409-9 · Cited by 89 · see citing works
Inhibition of RANKL-induced osteoclast formation in mouse bone marrow cells by IL-12: involvement of IFN-gamma possibly induced from non-T cell population.
Nagata, N., Kitaura, H., Yoshida, N., & Nakayama, K. (2003) · Bone · doi:10.1016/s8756-3282(03)00213-8 · Cited by 87 · see citing works
TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
Li, J., Ayoub, A., Xiu, Y., Yin, X., Sanders, J. O., Mesfin, A., Xing, L., Yao, Z., & Boyce, B. F. (2019) · Nature Communications · doi:10.1038/s41467-019-10677-0 · Cited by 86 · cited 4× · see citing works
“TRAF3 also inhibits OC formation indirectly by limiting NF-κB mediated RANKL production by MPCs [94].”
BackgroundInfluentialSelf-citation
TRAFs in RANK Signaling
Darnay, B. G., Besse, A., Poblenz, A. T., Lamothe, B., & Jacoby, J. J. (2007) · Springer eBooks · doi:10.1007/978-0-387-70630-6_12 · Cited by 84 · cited 2× · see citing works
“However, like other members of the TNF receptor super-family, RANK lacks intrinsic kinase activity to mediate downstream signaling [71].”
Background
Abaloparatide: A new pharmacological option for osteoporosis
Sleeman, A., & Clements, J. N. (2019) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/zxy022 · Cited by 82 · see citing works
RANKL cytokine enhances TNF-induced osteoclastogenesis independently of TNF receptor associated factor (TRAF) 6 by degrading TRAF3 in osteoclast precursors
Yao, Z., Lei, W., Duan, R., Li, Y., Luo, L., & Boyce, B. F. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.771816 · Cited by 75 · cited 7× · see citing works
“TGFβ1 Enhances TNF-induced OC formation independent of RANKL, RANK, and TRAF6 [87,93].”
BackgroundInfluentialSelf-citation
Treating osteoporosis by targeting parathyroid hormone to bone
Ponnapakkam, T., Katikaneni, R., Sakon, J., Stratford, R. E., & Gensure, R. C. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.07.015 · Cited by 72 · see citing works
Treatment of arthritis by macrophage depletion and immunomodulation: Testing an apoptosis‐mediated therapy in a humanized death receptor mouse model
Li, J., Hsu, H., Yang, P., Wu, Q., Li, H., Edgington‐Mitchell, L. E., Bogyo, M. S., Kimberly, R. P., & Mountz, J. D. (2011) · Arthritis & Rheumatism · doi:10.1002/art.33423 · Cited by 68 · see citing works
Interleukin-17 Induces an Atypical M2-Like Macrophage Subpopulation That Regulates Intestinal Inflammation
Nishikawa, K., Seo, N., Torii, M., Ma, N., Muraoka, D., Tawara, I., Masuya, M., Tanaka, K., Takei, Y., Shiku, H., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108494 · Cited by 64 · see citing works
Osteoblast and osteoclast cell number and cell activity in postmenopausal osteoporosis.
Gruber, H. E., Ivey, J. L., Thompson, E. R., Chesnut, C. H., & Baylink, D. J. (1986) · PubMed · Cited by 63 · see citing works
Effects of Anti-Tumor Necrosis Factor α (anti-TNF) agents on Bone
Kawai, V., Stein, C. M., Perrien, D., & Griffin, M. (2012) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e328356d212 · Cited by 63 · see citing works
Stimulation by TLR5 Modulates Osteoclast Differentiation through STAT1/IFN-β1
Ha, H., Lee, J.-H., Kim, H.-N., Kwak, H., Kim, H.-M., Lee, S.-E., Rhee, J., Kim, H.-H., & Lee, Z. (2008) · Journal of Immunology · doi:10.4049/jimmunol.180.3.1382 · Cited by 63 · see citing works
Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity
Nakanishi‐Matsui, M., Yano, S., Matsumoto, N., & Futai, M. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.07.050 · Cited by 62 · see citing works
Denosumab and atypical femoral fractures
Aspenberg, P. (2013) · Acta Orthopaedica · doi:10.3109/17453674.2013.859423 · Cited by 60 · cited 1× · see citing works
“Of concern is that bisphosphonates can result in atypical femoral fractures [16,17], hypocalcemia [18], and osteonecrosis of jaw bone [19,20] in a small number of patients.”
Background
TNF Induction of NF-κB RelB Enhances RANKL-Induced Osteoclastogenesis by Promoting Inflammatory Macrophage Differentiation but also Limits It through Suppression of NFATc1 Expression
Zhao, Z., Hou, X., Yin, X., Li, Y., Duan, R., Boyce, B. F., & Yao, Z. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135728 · Cited by 58 · cited 7× · see citing works
“IFN-γ and lipopolysaccharide (LPS) are traditionally considered as factors which polarize M1s [102], with GM-CSF and TNFα being the latest additions to M1 category of stimuli [98,102,152].”
BackgroundInfluentialSelf-citation
Expression of Either NF-κB p50 or p52 in Osteoclast Precursors Is Required for IL-1-Induced Bone Resorption
Xing, L., Carlson, L. M., Story, B. M., Tai, Z., Keng, P., Siebenlist, U. K., & Boyce, B. F. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.2.260 · Cited by 57 · see citing works
The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool
Lawal, R. A., Zhou, X., Batey, K., Hoffman, C. M., Georger, M. A., Radtke, F., Hilton, M. J., Xing, L., Frisch, B. J., & Calvi, L. M. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3106 · Cited by 53 · see citing works
Bisphosphonate therapy in rheumatoid arthritis
Breuil, V., & Euller‐Ziegler, L. (2006) · Joint Bone Spine · doi:10.1016/j.jbspin.2005.10.019 · Cited by 52 · cited 1× · see citing works
“In addition, both bisphosphonates and denosumab do not effectively prevent focal joint destruction in human RA [26,27].”
Background
Osteoporotic fracture trends in a population of US managed care enrollees from 2007 to 2017
Lewiecki, E. M., Chastek, B. J., Sundquist, K., Williams, S. A., Weiss, R. J., Wang, Y., Fitzpatrick, L. A., & Curtis, J. R. (2020) · Osteoporosis International · doi:10.1007/s00198-020-05334-y · Cited by 51 · cited 1× · see citing works
“However, the rate of osteoporotic fracture is no longer declining, and for some fracture types, the rates have been rising in recent years [15].”
Background
Jagged1 is essential for osteoblast development during maxillary ossification
Hill, C. R., Yuasa, M., Schoenecker, J. G., & Goudy, S. L. (2014) · Bone · doi:10.1016/j.bone.2014.01.019 · Cited by 48 · see citing works
Canonical Notch activation in osteocytes causes osteopetrosis
CANALIS, E. M., Bridgewater, D., Schilling, L., & Zanotti, S. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00395.2015 · Cited by 48 · see citing works
Cellular and humoral mechanisms of osteoclast formation in Ewing's sarcoma
Lau, Y.-S., Adamopoulos, I., Sabokbar, A., Giele, H., Gibbons, C. L., & Athanasou, N. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603774 · Cited by 47 · see citing works
Circulating amounts of osteoprotegerin and RANK ligand: Genetic influence and relationship with BMD assessed in female twins
Abrahamsen, B., Hjelmborg, J., Kostenuik, P. J., Stilgren, L. S., Kyvik, K. O., Adamu, S., Brixen, K., & Langdahl, B. L. (2005) · Bone · doi:10.1016/j.bone.2004.12.015 · Cited by 45 · cited 1× · see citing works
“However, some published data indicates that serum levels of RANKL are reduced [81,82] while OPG is increased [55,83,84] with aging and in postmenopausal osteoporotic women.”
Background
Mechanisms of bone fragility in a mouse model of glucocorticoid‐treated rheumatoid arthritis: Implications for insufficiency fracture risk
Takahata, M., Maher, J. R., Juneja, S. C., Inzana, J. A., Xing, L., Schwarz, E. M., Berger, A. J., & Awad, H. A. (2012) · Arthritis & Rheumatism · doi:10.1002/art.34639 · Cited by 45 · see citing works
Update on Glucocorticoid-Induced Osteoporosis
Maricic, M. J. (2011) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2011.07.003 · Cited by 44 · cited 1× · see citing works
“OC formation is increased, and its function on the trabecular surface is enhanced, resulting in systemic osteoporosis in RA, particularly in patients treated with corticosteroids [50,51].”
Background
Oral Bisphosphonate Related Osteonecrosis of the Jaw: A Challenging Adverse Effect
Benlidayı, İ. C., & Güzel, R. (2013) · ISRN Rheumatology · doi:10.1155/2013/215034 · Cited by 44 · see citing works
Long-Term Treatment With TNF-Alpha Inhibitors Improves Bone Mineral Density But Not Vertebral Fracture Progression in Ankylosing Spondylitis
Beek, K. J., Rusman, T., van der Weijden, M. A. C., Lems, W. F., van Denderen, J. C., Konsta, M. A. P., Visman, I. M., Nurmohamed, M. T., & van der Horst-Bruinsma, I. E. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3684 · Cited by 44 · see citing works
Modulation of Osteoclastogenesis with Macrophage M1- and M2-Inducing Stimuli
Jeganathan, S., Fiorino, C., Naik, U., Sun, H., & Harrison, R. E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104498 · Cited by 42 · see citing works
Accelerated alveolar bone loss in mice lacking interleukin‐10: late onset
Al‐Rasheed, A., Scheerens, H., Srivastava, A. K., Rennick, D. M., & Tatakis, D. N. (2004) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.2004.00724.x · Cited by 41 · see citing works
Glucocorticoid use in rheumatoid arthritis
Saag, K. G. (2002) · Current Rheumatology Reports · doi:10.1007/s11926-002-0068-z · Cited by 41 · cited 1× · see citing works
“OC formation is increased, and its function on the trabecular surface is enhanced, resulting in systemic osteoporosis in RA, particularly in patients treated with corticosteroids [50,51].”
Background
Bone Mineral Density Changes in Patients with Recent-Onset Rheumatoid Arthritis
Hafez, E. A., Mansour, H. E., Hamza, S. H., Moftah, S. G., Younes, T. B., & Ismail, M. A. (2011) · Clinical Medicine Insights Arthritis and Musculoskeletal Disorders · doi:10.4137/cmamd.s7773 · Cited by 38 · see citing works
Characterization of an early dendritic cell precursor derived from murine lineage-negative hematopoietic progenitor cells
Jackson, S. H., Alicea, C., Owens, J. W., Eigsti, C. L., & Malech, H. L. (2002) · Experimental Hematology · doi:10.1016/s0301-472x(02)00792-0 · Cited by 36 · see citing works
Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoetic stem cell transplantation
Pihusch, V., Pihusch, M., Penovici, M., Kolb, H. J., Hiller, E., & Pihusch, R. (2005) · Thrombosis Research · doi:10.1016/j.thromres.2004.12.010 · Cited by 36 · see citing works
Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in post-menopausal women
Uemura, H., Yasui, T., Miyatani, Y., Yamada, M., Hiyoshi, M., Arisawa, K., & Irahara, M. (2008) · Journal of Endocrinological Investigation · doi:10.1007/bf03345584 · Cited by 35 · cited 1× · see citing works
“However, some published data indicates that serum levels of RANKL are reduced [81,82] while OPG is increased [55,83,84] with aging and in postmenopausal osteoporotic women.”
Background
Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption
Thumbigere‐Math, V., Foster, B. L., Bachu, M., Yoshii, H., Brooks, S. R., Coulter, A. M., Chavez, M. B., Togi, S., Neely, A. L., Deng, Z., et al. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3690 · Cited by 35 · cited 4× · see citing works
“Consistent with these, mutation of the IRF8 gene promotes OC formation to increase the susceptibility to tooth root resorption in humans [97].”
BackgroundInfluential
Serum Levels of Receptor Activator of Nuclear Factor κB Ligand (RANKL) in Healthy Women and Men
Kerschan‐Schindl, K., Wendlová, J., Kudlacek, S., Gleiß, A., Woloszczuk, W., & Pietschmann, P. (2007) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-2007-993142 · Cited by 30 · cited 1× · see citing works
“However, some published data indicates that serum levels of RANKL are reduced [81,82] while OPG is increased [55,83,84] with aging and in postmenopausal osteoporotic women.”
Background
The world of biologics
Symmons, D. P. M., & Silman, A. J. (2006) · Lupus · doi:10.1191/0961203306lu2278rr · Cited by 28 · see citing works
Short-Term Effects of TNF Inhibitors on Bone Turnover Markers and Bone Mineral Density in Rheumatoid Arthritis
Orsolini, G., Adami, G., Adami, S., Viapiana, O., Idolazzi, L., Gatti, D., & Rossini, M. (2016) · Calcified Tissue International · doi:10.1007/s00223-016-0114-x · Cited by 26 · see citing works
Current Status of Bone-Forming Therapies for the Management of Osteoporosis
Sølling, A. S., Harsløf, T., & Langdahl, B. L. (2019) · Drugs & Aging · doi:10.1007/s40266-019-00675-8 · Cited by 25 · cited 2× · see citing works
“Therefore, the use of these anabolic treatments must be followed by anti-resorptive agents [28].”
Background
TNF-Polarized Macrophages Produce Insulin-like 6 Peptide to Stimulate Bone Formation in Rheumatoid Arthritis in Mice
Yi, X., Liu, X., Kenney, H. M., Duan, R., Lin, X., Schwarz, E. M., & Yao, Z. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4447 · Cited by 23 · see citing works
Self-citation
The impact of bisphosphonates on oral health: lessons from the past and opportunities for the future
Zavras, A. I. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05876.x · Cited by 20 · cited 1× · see citing works
“Of concern is that bisphosphonates can result in atypical femoral fractures [16,17], hypocalcemia [18], and osteonecrosis of jaw bone [19,20] in a small number of patients.”
Background
Effect of TNF inhibitors on bone mineral density in rheumatoid arthritis patients receiving bisphosphonate: a retrospective cohort study
Lee, J. S., Lim, D., Oh, J. S., Kim, Y., Lee, C., Yoo, B., & Hong, S. (2019) · Rheumatology International · doi:10.1007/s00296-019-04418-1 · Cited by 19 · see citing works
Does anti-TNF-alpha have a role in the treatment of osteoporosis?
McMahon, M. S., & Ueki, Y. (2008) · PubMed · Cited by 11 · see citing works
Symptomatic Hypocalcemia Associated with Zoledronic Acid Treatment for Osteoporosis: A Case Report
Elq, A. H. A. (2013) · Oman Medical Journal · doi:10.5001/omj.2013.42 · Cited by 8 · cited 1× · see citing works
“Of concern is that bisphosphonates can result in atypical femoral fractures [16,17], hypocalcemia [18], and osteonecrosis of jaw bone [19,20] in a small number of patients.”
Background
The protein tyrosine kinase p60c-Src is not implicated in the pathogenesis of the human autosomal recessive form of osteopetrosis: A study of 13 children
Bernard, F., Casanova, J., Cournot, G., Jabado, N., Peake, J., Jauliac, S., Fischer, A., & Hivroz, C. (1998) · The Journal of Pediatrics · doi:10.1016/s0022-3476(98)70064-2 · Cited by 7 · cited 1× · see citing works
“However, mutation of src kinase has not been identified in human patients with osteopetrosis [46,47].”
Background

Flagged first, then by citations

Sorted by citations

Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment
Wu, D., Luo, Y., Li, T., Zhao, X., Lv, T., Fang, G., Ou, P., Li, H., Luo, X., Huang, A., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1051082 · Cited by 271 · see citing works
“Inflammatory cytokines induce osteoclast maturation and inhibit osteoblast activation to perturb bone homeostasis, thus, anti-TNF therapy can improve bone homeostasis in RA patients (143, 144).”
Background
Insights and implications of sexual dimorphism in osteoporosis
Zhang, Y., Xie, N., Sun, X., Nice, E. C., Liou, Y., Huang, C., Zhu, H., & Shen, Z. (2024) · Bone Research · doi:10.1038/s41413-023-00306-4 · Cited by 160 · see citing works
“166,167 Estradiol also reduces in ﬂ ammation by downregulating the nuclear factor-κ B (NF-κ B) pathway, Fig.”
Background
Impact of the host response and osteoblast lineage cells on periodontal disease
Zhou, M., & Graves, D. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.998244 · Cited by 114 · see citing works
The RANK/RANKL/OPG system and tumor bone metastasis: Potential mechanisms and therapeutic strategies
Zhang, Y., Liang, J., Liu, P., Wang, Q., Liu, L., & Zhao, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1063815 · Cited by 111 · see citing works
Obesity and lipid metabolism in the development of osteoporosis (Review)
Wang, X., Zhang, C., Zhao, G.-T., Yang, K., & Tao, L. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5385 · Cited by 70 · see citing works
“TNF‑ α slows the differen‑ tiation of osteoblasts and enhances the activity of osteoclasts by recruiting TRAF and activating the NF‑ κ B/c‑Fos/nuclear factor of activated T‑cells cytoplasmic 1 (NFATc1) pathway, which is independent of the RANKL/RANK system (53,54).”
Background
Effect of Bifidobacterium on osteoclasts: TNF-α/NF-κB inflammatory signal pathway-mediated mechanism
Wu, Y., Yang, Y., Wang, L., Chen, Y., Han, X., Sun, L., Chen, H., & Chen, Q. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1109296 · Cited by 83 · see citing works
“explained the regulation of TNF-a-induced osteoclast formation (88).”
Background
Mechanistic advances in osteoporosis and anti‐osteoporosis therapies
Wang, H., Luo, Y., Wang, H., Li, F., Yu, F., & Ye, L. (2023) · MedComm · doi:10.1002/mco2.244 · Cited by 76 · see citing works
Plumbagin, a Natural Compound with Several Biological Effects and Anti-Inflammatory Properties
Petrocelli, G., Marrazzo, P., Bonsi, L., Facchin, F., Alviano, F., & Canaider, S. (2023) · Life · doi:10.3390/life13061303 · Cited by 75 · see citing works
Inflammatory bone loss and signaling pathways in periodontitis: mechanistic insights and emerging therapeutic strategies
de Molon, R. S., Vernal, R., Oliveira, G. E., Steffens, J. P., Ervolino, E., Theodoro, L. H., van den Beucken, J. J. J. P., & Tetradis, S. (2026) · Bone Research · doi:10.1038/s41413-025-00478-1 · Cited by 83 · see citing works
IRF8: Mechanism of Action and Health Implications
Moorman, H. R., Reategui-Almonacid, Y., Poschel, D. B., & Liu, K. (2022) · Cells · doi:10.3390/cells11172630 · Cited by 63 · see citing works
Role and Regulation of Transcription Factors in Osteoclastogenesis
Jiang, T., Xia, T., Qiao, F., Wang, N., Jiang, Y., & Xin, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216175 · Cited by 60 · see citing works
“The differentiation of osteoclasts is primarily dependent on a tumor necrosis factor (TNF) family, RANK, RANKL, osteoprotegerin (OPG), and M-CSF [53,54].”
Background
Cell signaling and transcriptional regulation of osteoclast lineage commitment, differentiation, bone resorption and diseases
Zhu, S., Yan, M.-Q., Masson, A., Chen, W. "., & Li, Y. (2026) · Cell Discovery · doi:10.1038/s41421-025-00853-6 · Cited by 64 · see citing works
“Recent evidence identi ﬁ es RBP-J as a critical negative regulator that restrains osteoclast differentiation and limits excessive bone resorption in TNF-driven in ﬂ ammatory settings 82 .”
Influential
Osteoclasts and osteoarthritis: Novel intervention targets and therapeutic potentials during aging
Wang, H., Yuan, T., Wang, Y., Liu, C., Li, D., Li, Z., & Sun, S. (2024) · Aging Cell · doi:10.1111/acel.14092 · Cited by 60 · see citing works
“The inflammatory microenvironment and the SASP that secreted, such as IL-1, IL-6, IL-17, and tumor necrosis factor-α (TNF-α ) exhibit a positive regulatory effect on osteo-clast differentiation and function (Son et al., 2020; Yao et al., 2021; Yokota et al., 2021; Zhang et al., 2019).”
Background
The role of TNF-α in osteoporosis, bone repair and inflammatory bone diseases: A review
yao, Q., He, L., Bao, C., yan, X., & Jun, A. (2024) · Tissue and Cell · doi:10.1016/j.tice.2024.102422 · Cited by 57 · see citing works
New mechanistic understanding of osteoclast differentiation and bone resorption mediated by P2X7 receptors and PI3K-Akt-GSK3β signaling
Lu, J., Shi, X., Fu, Q., Han, Y., Zhu, L., Zhou, Z., Li, Y., & Lu, N. (2024) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00614-5 · Cited by 54 · see citing works
“Osteoclasts play a critical role in the development of OP, and their differentiation and activity are crucial for the regulation of bone resorption [15, 16].”
Background
Role of Enterococcus faecalis in refractory apical periodontitis: from pathogenicity to host cell response
Deng, Z., Lin, B., Liu, F., & Zhao, W. (2023) · Journal of Oral Microbiology · doi:10.1080/20002297.2023.2184924 · Cited by 53 · see citing works
“Osteoclast activation and differentiation are regulated by three members of the TNF ligand and receptor superfamily: osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), and RANK [97].”
BackgroundInfluential
Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases
Wang, X.-X., Sun, B., Wang, Y., Gao, P., Song, J., Chang, W., Xiao, Z., Xi, Y., Li, Z., An, F.-Y., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1333993 · Cited by 59 · see citing works
“…107), TNF-a can improve OC production by coordinating with RANKL and increasing RANK expression of OC precursor (33), and also indirectly stimulate OC development and function by reducing OPG release from OBs (108), indicating that Th17 cells also indirectly increase OC by reducing OPG/RANKL ratio.”
BackgroundInfluential
Pharmacological and mechanistic aspects of quercetin in osteoporosis
Deng, T., Ding, W., Lu, X.-X., Zhang, Q., Du, J.-X., Wang, L., Yang, M., Yin, Y., & Liu, F.-J. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1338951 · Cited by 51 · see citing works
“…et al., 2018; Lee et al., 2018; Luo et al., 2018; Noguchi et al., 2018; Ha and Choung, 2020; Kurotaki et al., 2020; Yang et al., 2020; Udagawa et al., 2021; Velletri et al., 2021; Yao et al., 2021). other bioactive ingredients has shown synergistic anti-osteoporotic effects (Rayalam et al., 2011).”
Background
Association of systemic inflammatory response index with bone mineral density, osteoporosis, and future fracture risk in elderly hypertensive patients
Ma, H., Cai, X., Hu, J., Song, S., Zhu, Q., Zhang, Y., Ma, R., Shen, D., Yang, W., Zhou, P., et al. (2024) · Postgraduate Medicine · doi:10.1080/00325481.2024.2354158 · Cited by 47 · see citing works
“Furthermore, it inhibits the release of osteoprotegerin, thereby attenuating the inhibition of osteoclast activity [72].”
Background
Protease-Loaded CuS Nanoparticles with Synergistic Photothermal/Dynamic Therapy against F. nucleatum-Induced Periodontitis
Gao, P., Li, G., Wang, Z., Zhang, H., Shan, Y., Yuan, X., Shi, Q., Dou, X., Zhou, Q., & Xu, Q. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c04534 · Cited by 45 · see citing works
Targeting transcription factors for therapeutic benefit in rheumatoid arthritis
Balendran, T., Lim, K. K. T., Hamilton, J. A., & Achuthan, A. A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1196931 · Cited by 45 · see citing works
“NFATC1 is a major TF that regulates osteoclast differentiation (25).”
Background
Liver-bone crosstalk in non-alcoholic fatty liver disease: Clinical implications and underlying pathophysiology
Zhao, J.-H., Lei, H.-Y., Wang, T.-Y., & Xiong, X. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1161402 · Cited by 45 · see citing works
“In addition, TNF-a suppresses recruitment of osteoblasts from progenitor cells and inhibits osteoblast differentiation (82, 83).”
Background
Revisiting Resveratrol as an Osteoprotective Agent: Molecular Evidence from In Vivo and In Vitro Studies
Hairi, H. A., Jayusman, P. A., & Shuid, A. N. (2023) · Biomedicines · doi:10.3390/biomedicines11051453 · Cited by 39 · see citing works
Cellular interactions in maintaining an inflammatory microenvironment in rheumatoid arthritis
Ganeshalingam, S., Wilson, N. J., Ciciriello, S., Antonipillai, J., & Achuthan, A. A. (2025) · Molecular Immunology · doi:10.1016/j.molimm.2025.06.008 · Cited by 38 · see citing works
Targeting STING: From antiviral immunity to treat osteoporosis
Gao, Z., Gao, Z., Zhang, H., Hou, S., Zhou, Y., & Liu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1095577 · Cited by 37 · see citing works
Osteoporosis: interferon-gamma-mediated bone remodeling in osteoimmunology
Li, S., Liu, G., & Hu, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1396122 · Cited by 41 · see citing works
“…and transmits RANK stimulation to NF-k B (85), which activates and translocates NF-k B into the nucleus, increasing the expression of c-Fos. c-Fos activates the expression of NFATc1, initiates osteoclastogenic gene transcription, ultimately inducing the formation of mature osteoclasts (94, 95).”
Icariin-loaded sulfonated polyetheretherketone with osteogenesis promotion and osteoclastogenesis inhibition properties via immunomodulation for advanced osseointegration
Chai, H., Sang, S., Luo, Y., He, R., Yuan, X., & Zhang, X. (2022) · Journal of Materials Chemistry B · doi:10.1039/d1tb02802b · Cited by 36 · see citing works
Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature
Zhao, S., Qiao, Z., Pfeifer, R., Pape, H.-C., Mao, K., Tang, H., Meng, B., Chen, S., & Liu, H. (2024) · European Journal of Medical Research · doi:10.1186/s40001-023-01604-7 · Cited by 35 · see citing works
Targeting Sirt1, AMPK, Nrf2, CK2, and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass
McCarty, M. F., Luján, L. M. L., & Assanga, S. B. I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094776 · Cited by 34 · see citing works
Subchondral osteoclasts and osteoarthritis: new insights and potential therapeutic avenues
Chen, W., Wang, Q., Tao, H., Lu, L., Zhou, J., Wang, Q., Huang, W., & Yang, X. H. (2024) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2024017 · Cited by 35 · see citing works
“The role of OCs in OA formation, and several inhibitory proteins, including TRAF3, IRF8, and RBP-j, regulate this process [135].”
Background
Flavonoid extract from propolis alleviates periodontitis by boosting periodontium regeneration and inflammation resolution via regulating TLR4/MyD88/NF-κB and RANK/NF-κB pathway
Tang, M., Wang, G., Li, J., Wang, Y., Peng, C., Chang, X., Guo, J. X., & Gui, S. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117324 · Cited by 31 · see citing works
Beyond the Brain: Exploring the multi-organ axes in Parkinson’s disease pathogenesis
Liu, T., Wu, H., & Wei, J. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.05.034 · Cited by 30 · see citing works
“OPG, a TNF receptor superfamily member, maintains bone homeostasis through osteoclast regulation [178].”
Mechanistic and therapeutic links between rheumatoid arthritis and diabetes mellitus
Li, J., Chen, Y., Liu, Q., Tian, Z., & Zhang, Y. (2022) · Clinical and Experimental Medicine · doi:10.1007/s10238-022-00816-1 · Cited by 29 · see citing works
“TNF-α stimulates the synthesis of prostaglandin E2 (PGE2) from synovial cells and chondrocytes, leading to blood vessels extravasation and osteoclast-mediated osteolysis and joint damage [24, 25].”
Background
Role of histone modification in the occurrence and development of osteoporosis
Sun, P., Huang, T., Huang, C., Wang, Y., & Tang, D. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.964103 · Cited by 28 · see citing works
From death to birth: how osteocyte death promotes osteoclast formation
Zhao, W., Qian, J., Li, J., Su, T., Deng, X., Fu, Y., Liang, X., & Cui, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1551542 · Cited by 26 · see citing works
“These mononuclear cells with potential to form osteoclasts are called osteoclast precursors (OCPs) and located in multiple tissue, including bone marrow, spleen, thymus, or peripheral blood (18).”
CCL2 is a key regulator and therapeutic target for periodontitis
Jiang, W., Xu, T., Song, Z., Wang, X., Yuan, S., Li, Q., Wei, Y., Wang, C., Yang, G., Cao, J., et al. (2023) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13872 · Cited by 26 · see citing works
Macrophages in the process of osseointegration around the implant and their regulatory strategies
Fang, X., Sun, D., Li, Y., Han, X., Gan, Y.-L., Jiao, J., Jiang, M., Gong, H., Qi, Y., & Zhao, J.-H. (2024) · Connective Tissue Research · doi:10.1080/03008207.2023.2300455 · Cited by 21 · see citing works
“In contrast to the mechanism of RANK-induced osteoclast survival, the ability of TNF-α to induce OC differentiation can be enhanced by TGF-β1 or IL-1β independently of RANKL, tumor necrosis factor-associated protein 6 (TRAF6)/NF-κB 47 .”
Background
Corylifol A protects against ovariectomized-induced bone loss and attenuates RANKL‐induced osteoclastogenesis via ROS reduction, ERK inhibition, and NFATc1 activation
Xu, Y., Song, D., Lin, X., Peng, H., Su, Y., Liang, J., Hai, N., Zhao, J., & Liu, Q. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.01.017 · Cited by 25 · see citing works
Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway
Liu, K., Wang, Z., Liu, J., Zhao, W. H., Qiao, F., He, Q., Shi, J., Meng, Q., Wei, J., & Cheng, L. (2023) · Communications Biology · doi:10.1038/s42003-023-05635-y · Cited by 24 · see citing works
“TNF-α is reported to play a predominant role in osteoclastogenesis 14,24,25 .”
Background
Osteoclasts in Osteosarcoma: Mechanisms, Interactions, and Therapeutic Prospects
Gao, Y.-M., Pei, Y., Zhao, F.-F., & Wang, L. (2023) · Cancer Management and Research · doi:10.2147/cmar.s431213 · Cited by 23 · see citing works
Targeting bone homeostasis regulation: potential of traditional Chinese medicine flavonoids in the treatment of osteoporosis
Du, J., Wang, Y., Wu, C., Zhang, X., Zhang, X., & Xu, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1361864 · Cited by 21 · see citing works
Enterococcal-host interactions in the gastrointestinal tract and beyond
Madani, W. A. M., Ramos, Y., Cubillos‐Ruiz, J. R., & Morales, D. K. (2024) · FEMS Microbes · doi:10.1093/femsmc/xtae027 · Cited by 21 · see citing works
The Role of Cytokines in Orthodontic Tooth Movement
Kitaura, H., Ohori, F., Marahleh, A., Ma, J., Lin, A., Fan, Z., Narita, K., Murakami, K., & Kanetaka, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146688 · Cited by 21 · see citing works
“TNF-α mediates osteoclast formation in vitro and in vivo [193].”
The role of the cGAS-STING pathway in metabolic diseases
Xu, Q., Xing, J., Wang, S., Peng, H., & Liu, Y. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33093 · Cited by 21 · see citing works
“Notably, IFN-β is also a downstream target of STING and can negatively regulate osteoclast activation through a feedback mechanism [63].”
Background
The cross-talk between the cGAS-STING signaling pathway and chronic inflammation in the development of musculoskeletal disorders
Kalinkovich, A., & Livshits, G. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102602 · Cited by 22 · see citing works
The association between sex hormones and bone mineral density in US females
Tian, X., & Zhang, B. (2025) · Scientific Reports · doi:10.1038/s41598-025-89985-z · Cited by 19 · see citing works
Research progress on osteoclast regulation by biodegradable magnesium and its mechanism
Zhu, W., Wang, W., Yang, X. H., Ran, C., Zhang, T., Shibo, H., Yang, J., Wang, F., Wang, H., Wan, P., et al. (2025) · Regenerative Biomaterials · doi:10.1093/rb/rbaf026 · Cited by 19 · see citing works
Genistein and coumestrol reduce MCF-7 breast cancer cell viability and inhibit markers of preferential metastasis, bone matrix attachment and tumor-induced osteoclastogenesis
Mezban, S. G., & Fox, S. W. (2023) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2023.109583 · Cited by 18 · see citing works
Pteryxin suppresses osteoclastogenesis and prevents bone loss via inhibiting the MAPK/Ca2+ signaling pathways mediated by ROS
Sun, R., Hai, N., Yang, B., Chen, J., Li, J., Li, Q., Zhao, J., Xu, J., Liu, Q., & Zhou, B. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114898 · Cited by 18 · see citing works
Mechanism of action of gut microbiota and probiotic Lactobacillus rhamnosus GG on skeletal remodeling in mice
Tyagi, A. M. (2023) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.440 · Cited by 18 · see citing works
Bone marrow adipocytes and lung cancer bone metastasis: unraveling the role of adipokines in the tumor microenvironment
Li, J., Wu, J., Xie, Y., & Yu, X. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1360471 · Cited by 18 · see citing works
“OPG, a competitive receptor for RANKL, inhibits the RANKL-RANK interaction, thereby reducing OC formation and activity (63).”
Background
Signal pathways in the treatment of Rheumatoid Arthritis with traditional Chinese medicine
Wang, S., Zhang, J., Liu, W., Zhang, L., Li, R., Wang, Y., Li, S., Li, L., Li, J., Zhou, M., et al. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120387 · Cited by 17 · see citing works
Role of the major histocompatibility complex class II protein presentation pathway in bone immunity imbalance in postmenopausal osteoporosis
Wang, X., Zhang, X., Han, Y.-D., Duan, X., Wang, J., Yan, H., Wang, S.-S., Xu, Y., Zhu, Z.-S., Wang, L., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.876067 · Cited by 14 · see citing works
Betulinic Acid Attenuates Osteoarthritis via Limiting NLRP3 Inflammasome Activation to Decrease Interleukin-1β Maturation and Secretion
Liu, B., Wu, Y., Liang, T., Zhou, Y., Chen, G., He, J., Ji, C., Liu, P., Zhang, C., Lin, J., et al. (2023) · Mediators of Inflammation · doi:10.1155/2023/3706421 · Cited by 17 · see citing works
Disulfidptosis-related Protein RPN1 may be a Novel Anti-osteoporosis Target of Kaempferol
Pan, C., Zhang, C., Lin, Z., Liang, Z., Cui, Y., Shang, Z., Wei, Y., & Chen, F. (2024) · Combinatorial Chemistry & High Throughput Screening · doi:10.2174/0113862073273655231213070619 · Cited by 17 · see citing works
Dehydromiltirone inhibits osteoclast differentiation in RAW264.7 and bone marrow macrophages by modulating MAPK and NF-κB activity
Deng, W., Huang, Y., Li, H., Chen, C., Lin, Y., Wang, M., Huang, H., Liu, T., Qin, Q., Shao, Y., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1015693 · Cited by 17 · see citing works
“However, after RANKL stimulation, NF-κB is degraded and released into the cytoplasm, inducing the generation of mature osteoclasts (Lawrence, 2009; Yao et al., 2021).”
Background
Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice
Shen, G., Liu, X., Lei, W., Duan, R., & Yao, Z. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101767 · Cited by 19 · see citing works
“This is an open access article under the CC NF-κB family of transcriptional factors plays a central role in OC differentiation by sequentially activating c-Fos followed by NFATc1 (19, 20), the two other transcriptional factors critical for OC differentiation; (2) NIK, the key kinase that activates noncanonical NF-κB s…”
BackgroundSelf-citation
Babam2 negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription
Jin, F., Zhu, Y., Liu, M., Wang, R., Cui, Y., Wu, Y., Liu, G., Wang, Y., Wang, X., & Ren, Z. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.72487 · Cited by 16 · see citing works
“As TNF family mediated signaling is implicated in regulating bone resorption [31, 32], it promotes us to explore the role of Babam2 modulation in osteoclast formation.”
Background
Tumor necrosis factor α and its role in pathologies
Терещенко, И. В., & Каюшев, П. Е. (2022) · Russian Medical Inquiry · doi:10.32364/2587-6821-2022-6-9-523-527 · Cited by 16 · see citing works
Research Advances on Stem Cell-Derived Extracellular Vesicles Promoting the Reconstruction of Alveolar Bone through RANKL/RANK/OPG Pathway
Huang, X., Li, Y., Liao, H., Luo, X., Zhao, Y., Huang, Y., Zhou, Z., & Xiang, Q. (2023) · Journal of Functional Biomaterials · doi:10.3390/jfb14040193 · Cited by 15 · see citing works
Isolation and characterization of a novel homopolysaccharide (SFP-1) from Sargassum fusiforme: Promising anti-osteoporosis activity by modulating adipo-osteogenic differentiation
Deng, L.-M., Feng, Z., Zheng, H., Li, X., Wu, X., Quan, W., Zhu, Y., Liao, J., Wu, K., & Luo, H. (2023) · Industrial Crops and Products · doi:10.1016/j.indcrop.2023.117749 · Cited by 15 · see citing works
The Potential of Natural Compounds Regulating Autophagy in the Treatment of Osteoporosis
Zhao, Y., Qu, Z., Zhao, S., Zhang, Y., Gong, Y., Zhang, B., Gao, X., Wang, D., & Yan, L. W. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s437067 · Cited by 15 · see citing works
“48, 81 According to reports in the literature, OPG inhibits OCs differentiation and bone resorption by enhancing autophagy in vitro, and the mechanism is that OPG activates AMPK protein, which regulates OCs autophagy through the AMPK/ mTOR/p70S6K pathway.”
Background
Developmental Toxicity of PEDOT:PSS in Zebrafish: Effects on Morphology, Cardiac Function, and Intestinal Health
Yang, G., Gou, D., Bu, L.-K., Wei, X., Hu, H., Huo, W., Sultan, M., & Pei, D. (2024) · Toxics · doi:10.3390/toxics12020150 · Cited by 15 · see citing works
Bone Health Impairment in Patients with Hemoglobinopathies: From Biological Bases to New Possible Therapeutic Strategies
Paola, A. D., Marrapodi, M. M., Martino, M. D., Giliberti, G., Feo, G. D., Rana, D., Ahmed, S., Argenziano, M., Rossi, F., & Roberti, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052902 · Cited by 15 · see citing works
“OCs are terminally differentiated multinucleated cells localized on the trabecular surface [53,54].”
Background
Synergistic roles of tristetraprolin family members in myeloid cells in the control of inflammation
Snyder, B. L., Huang, R., Burkholder, A., Donahue, D., Mahler, B. W., Bortner, C. D., Lai, W. S., & Blackshear, P. J. (2023) · Life Science Alliance · doi:10.26508/lsa.202302222 · Cited by 14 · see citing works
“…of the severe M-triple KO syndrome, and their involvement in in-ﬂ ammatory diseases and disease models has been documented in many previous studies (Deshmane et al, 2009; Lee et al, 2017; Karin & Razon, 2018; Steinkamp et al, 2018; Tokunaga et al, 2018; House et al, 2020; Yao et al, 2021).”
Background
Advancements in bone organoids: perspectives on construction methodologies and application strategies
Huang, S., Wu, Y., Zhao, H., Song, K., Liu, Y., Mao, J., & Li, Q. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.06.011 · Cited by 16 · see citing works
“Several factors inﬂuence the differentiation of OCs, and macrophage colony-stimulating factor (M − CSF) secreted by OBs and MSCs, and receptor activator of nuclear factor-j B ligand (RANKL) secreted by OBs and OCs, are the two key cytokines that regulate their differentiation [32].”
A review: the mechanism of plant-derived polysaccharides on osteoblasts and osteoclasts
Ren, M., Ahmed, A. F., Li, M., Li, M., Yan, Z., & Wang, J. (2023) · Journal of Future Foods · doi:10.1016/j.jfutfo.2023.07.001 · Cited by 14 · see citing works
Uncovering the mechanisms of Zhubi decoction against rheumatoid arthritis through an integrated study of network pharmacology, metabolomics, and intestinal flora
Liu, J., Li, B., Zhou, X., Liu, G., Li, C., Hu, Z., & Peng, R. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118736 · Cited by 14 · see citing works
Self‐Replenishable Metabolically Augmented Synbiotic Microspheres Remodel Gut‐Bone Homeostasis
Chen, Z., Liu, H., Chen, Y., Tang, Y., Tang, Y., Sarmento, B. F. C. C., He, C., Cai, Z., & Cui, W. (2025) · Advanced Materials · doi:10.1002/adma.202500746 · Cited by 14 · see citing works
pH-responsive cinnamaldehyde-TiO2 nanotube coating: fabrication and functions in a simulated diabetes condition
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Authors: Yao, Z., Getting, S. J., & Locke, I. C.
Affiliations: University of Rochester Medicine (US)
University of Westminster (GB)
Corresponding author: Yao, Zhenqiang
ORCID: Yao, Zhenqiang
Getting, Stephen J.
Locke, Ian C.
Venue: Cells
Publisher: MDPI AG
Published: 2021-12-31
Volume: 11
Issue: 1
Pages: 132
ISSN: 2073-4409 (ISSN-L)
DOI: 10.3390/cells11010132
PMC: PMC8750957
OpenAlex: W4205952184
Cited by: 280
References: 201
Citations by year: 2026: 45 · 2025: 87 · 2024: 69 · 2023: 54 · 2022: 25
FWCI: 3.88
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cells (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
WestminsterResearch (University of Westminster) (acceptedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute on Aging (AG049994)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Keywords: TNF-α, osteoclastogenesis, TNF receptor-associated factors, NF-κB signaling, NFATc1, TRAF3, interleukin-1, TGF-β1, osteoporosis, rheumatoid arthritis, bone loss, antiresorptive agents, Jagged1, macrophages
MeSH terms: Animals, Arthritis, Rheumatoid, Cell Differentiation, Humans, Osteoclasts, Osteoporosis, Tumor Necrosis Factor-alpha, Signal Transduction

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Regulation of TNF-Induced Osteoclast Differentiation

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