Finding a Toll on the Route: The Fate of Osteoclast Progenitors After Toll-Like Receptor Activation
Open accessAbstract
M-CSF and RANKL are two crucial cytokines stimulating differentiation of mature, bone resorbing, multinucleated osteoclasts from mononucleated progenitor cells in the monocyte/macrophage lineage. In addition to the receptors for M-CSF and RANKL, osteoclast progenitor cells express receptors for several other pro- and anti-osteoclastogenic cytokines, which also regulate osteoclast formation by affecting signaling downstream M-CSF and RANKL receptors. Similar to many other cells originating from myeloid hematopoetic stem cells, also osteoclast progenitors express toll-like receptors (TLRs). Nine murine TLRs are expressed in the progenitors and all, with the exception of TLR2 and TLR4, are downregulated during osteoclastogenesis. Activation of TLR2, TLR4 and TLR9, but not TLR5, in osteoclast progenitors stimulated with M-CSF and RANKL arrests differentiation along the osteoclastic lineage and keeps the cells at a macrophage stage. When the progenitors are primed with M-CSF/RANKL and then stimulated with agonists for TLR2, TLR4 or TLR9 in the presence of M-CSF, but in the absence of RANKL, the cells differentiate to mature, bone resorbing osteoclasts. TLR 2, 4, 5 and 9 are also expressed on osteoblasts and their activation increases osteoclast differentiation by an indirect mechanism through stimulation of RANKL. In mice, treatment with agonists for TLR2, 4 and 5 results in osteoclast formation and extensive bone loss. It remains to be shown the relative importance of inhibitory and stimulatory effects by TLRs on osteoclast progenitors and the role of RANKL produced by TLR stimulated osteoblasts, for the bone resorbing effects in vivo.
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TLRs expressed on osteoclast progenitors promote differentiation toward the mature cell phenotype, as observed in inflammatory osteolytic diseases.
“Additionally, Toll-like receptors (TLRs) expressed on osteoclast progenitors178 promote differentiation toward the mature cell phenotype, as observed in inflammatory osteolytic diseases.179”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [178]
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“coli LPS, increases the survival of mature osteoclasts (72, 76, 99), an observation not seen by adding agonists activating TLR3 or TLR9.”
Is serum amyloid A an endogenous TLR4 agonist?
Sandri, S., Rodriguez, D., Gomes, E., Monteiro, H. P., Russo, M., & Campa, A. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0407203 · Cited by 188 · cited 1× · see citing works
“Thus, TLR4, as an example, can recognize MAMPs such as lipopolysaccharide LPS (41) and lipid A (42), as well as DAMPs such as serum amyloid A (43), S100A8/S100A9 (44), oxidized low-density lipoprotein and amyloid β (45), in addition to several other MAMPs and DAMPs.”
BackgroundAnti-tumor Activity of Toll-Like Receptor 7 Agonists
Chi, H., Li, C., Zhao, F. S., Zhang, L., Ng, T. B., Jin, G., & Sha, O. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00304 · Cited by 182 · cited 1× · see citing works
“TLR7 can also be targeted by the synthetic compound imiquimod, used for topical treatment of skin cancers and other cutaneous disorders (55).”
BackgroundInterferon-Gamma-Mediated Osteoimmunology
Tang, M., Tian, L., Luo, G., & Yu, X. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01508 · Cited by 159 · see citing works
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Ji, J.-D., Park‐Min, K., Shen, Z., Fajardo, R. J., Goldring, S. R., McHugh, K. P., & Ivashkiv, L. B. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900072 · Cited by 158 · cited 14× · see citing works
“coli LPS activating TLR4, or CpG motif of unmethylated DNA (Cpg-ODN) activating TLR9, blocks RANKL-induced osteoclastogenesis in M-CSF-treated mouse bone marrow macrophage cultures (72, 75, 76, 84).”
BackgroundInfluentialDynamic lipopolysaccharide transfer cascade to TLR4/MD2 complex via LBP and CD14
Kim, S. J., & Kim, H. M. (2017) · BMB Reports · doi:10.5483/bmbrep.2017.50.2.011 · Cited by 153 · cited 1× · see citing works
“In the case of TLR4, recognition of LPS requires binding to the accessory proteins LPS-binding protein and CD14 before being transferred to the TLR4/MD2 protein complex (47).”
BackgroundSato, N., Takahashi, N., Suda, K., Nakamura, M., Yamaki, M., Ninomiya, T., Kobayashi, Y., Takada, H., Shibata, K., Yamamoto, M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040689 · Cited by 132 · see citing works
Kassem, A. M., Henning, P., Lundberg, P., de Souza, P. C., Lindholm, C., & Lerner, U. H. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655787 · Cited by 130 · see citing works
Self-citationNaldini, A., Carraro, F., Silvestri, S., & Bocci, V. A. (1997) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199712)173:3 · Cited by 118 · see citing works
Lin, J., Bi, L., Yu, X., Kawai, T., Taubman, M. A., Shen, B., & Han, X. (2014) · Infection and Immunity · doi:10.1128/iai.02084-14 · Cited by 118 · cited 1× · see citing works
“gingivalis LPS utilizes TLR2 to induce osteoclastogenesis (70, 71).”
BackgroundMolecular Mechanism of the Bifunctional Role of Lipopolysaccharide in Osteoclastogenesis*
Liu, J.-Z., Wang, S.-Q., Zhang, P., Said-Al-Naief, N., Michalek, S., & Feng, X. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809789200 · Cited by 115 · cited 6× · see citing works
“coli LPS activating TLR4, or CpG motif of unmethylated DNA (Cpg-ODN) activating TLR9, blocks RANKL-induced osteoclastogenesis in M-CSF-treated mouse bone marrow macrophage cultures (72, 75, 76, 84).”
BackgroundInfluentialZhang, P., Liu, J., Xu, Q., Harber, G. J., Feng, X., Michalek, S. M., & Katz, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.198085 · Cited by 114 · see citing works
Taking a Toll on the bones: Regulation of bone metabolism by innate immune regulators
Bar‐Shavit, Z. (2008) · Autoimmunity · doi:10.1080/08916930701694469 · Cited by 107 · cited 1× · see citing works
“Using purified bone marrow macrophages/osteoclast progenitors, however, it has been shown that LPS can both inhibit and stimulate osteoclastogenesis dependent on the differentiation level of the progenitors (73).”
BackgroundHou, L., Sasaki, H., & Stashenko, P. (2000) · Infection and Immunity · doi:10.1128/iai.68.8.4681-4687.2000 · Cited by 106 · cited 1× · see citing works
“Following the discovery of TLRs, it has been found that LPS from several bacteria stimulates osteoclast formation and bone resorption in vivo through activation of TLR4 (68, 69), whereas P.”
BackgroundKim, J., Yang, J., Park, O.-J., Kang, S., Kim, W.-S., Kurokawa, K., Yun, C., Kim, H., Lee, B. L., & Han, S. H. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1973 · Cited by 105 · see citing works
Zou, W., Amcheslavsky, A., & Bar‐Shavit, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212473200 · Cited by 97 · cited 2× · see citing works
“coli LPS and CpG-ODN stimulated the expression of TNF-α and activated NF-κB, ERK1/2 and p38 (101).”
BackgroundIshihara, Y., Nishihara, T., Maki, E., Noguchi, T., & Koga, T. (1991) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.1991.tb01639.x · Cited by 91 · see citing works
Putnam, N. E., Fulbright, L. E., Curry, J. M., Ford, C. A., Petronglo, J. R., Hendrix, A. S., & Cassat, J. E. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007744 · Cited by 86 · cited 1× · see citing works
“Bacteria-induced bone loss is also involved in the pathogenesis of osteomyelitis (10).”
BackgroundKassem, A., Lindholm, C., & Lerner, U. H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0156708 · Cited by 71 · cited 14× · see citing works
“In agreement with the fact that increased formation of inflammatory cytokines is a well-known, Myd88-dependent, phenomenon in macrophages stimulated by TLR agonist, it has been observed that activation of BMMs with peptidoglycan, poly(I:c)dsRNA, E. coli LPS, CpG-ODN results in increased expression of TNF-α (72, 75).”
BackgroundInfluentialSelf-citationCpG oligonucleotides: novel regulators of osteoclast differentiation
Zou, W., Schwartz, H., Endres, S., Hartmann, G., & Bar-Shavit, Z. (2002) · The FASEB Journal · doi:10.1096/fj.01-0586com · Cited by 66 · see citing works
Peng, Q., Long, C. L., Malhotra, S., & Humphrey, M. B. (2013) · Science Signaling · doi:10.1126/scisignal.2003801 · Cited by 64 · see citing works
Orcel, P., Feuga, M., Bielakoff, J., & de Vernejoul, M. C. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.264.3.e391 · Cited by 63 · see citing works
Interleukin (IL)‐12 mediates the anti‐osteoclastogenic activity of CpG‐oligodeoxynucleotides
Amcheslavsky, A., & Bar‐Shavit, Z. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20563 · Cited by 60 · cited 8× · see citing works
“In agreement with the fact that increased formation of inflammatory cytokines is a well-known, Myd88-dependent, phenomenon in macrophages stimulated by TLR agonist, it has been observed that activation of BMMs with peptidoglycan, poly(I:c)dsRNA, E. coli LPS, CpG-ODN results in increased expression of TNF-α (72, 75).”
BackgroundInfluentialHayashi, S., Yamada, T., Tsuneto, M., Yamane, T., Takahashi, M., Shultz, L. D., & Yamazaki, H. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.5130 · Cited by 53 · cited 9× · see citing works
“Thus, TLR4, as an example, can recognize MAMPs such as lipopolysaccharide LPS (41) and lipid A (42), as well as DAMPs such as serum amyloid A (43), S100A8/S100A9 (44), oxidized low-density lipoprotein and amyloid β (45), in addition to several other MAMPs and DAMPs.”
BackgroundInfluentialTLR5, a novel mediator of innate immunity‐induced osteoclastogenesis and bone loss
Kassem, A. M., Henning, P., Kindlund, B., Lindholm, C., & Lerner, U. H. (2015) · The FASEB Journal · doi:10.1096/fj.15-272559 · Cited by 49 · cited 4× · see citing works
“A similar increase of Tnfsf11 mRNA and decrease of Opg mRNA can be seen in mice treated with flagellin, causing increased osteoclast formation and extensive bone loss in wild type, but not in Tlr5 mice (85).”
BackgroundInfluentialSelf-citationChen, Z., Su, L., Xu, Q., Katz, J., Michalek, S. M., Fan, M., Feng, X., & Zhang, P. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.663518 · Cited by 47 · cited 1× · see citing works
“gingivalis LPS, enhanced osteoclast formation induced by RANKL (81).”
BackgroundNakamura, H., 由紀子, 福., Yoshimura, A., Shiraishi, C., Kishimoto, M., Kaneko, T., & Hara, Y. (2008) · Oral Microbiology and Immunology · doi:10.1111/j.1399-302x.2007.00410.x · Cited by 46 · cited 1× · see citing works
“Following the discovery of TLRs, it has been found that LPS from several bacteria stimulates osteoclast formation and bone resorption in vivo through activation of TLR4 (68, 69), whereas P.”
BackgroundDirect Inhibition of Human RANK+ Osteoclast Precursors Identifies a Homeostatic Function of IL-1β
Lee, B., Kim, T., Jun, J., Yoo, D., Woo, J.-H., Choi, S. J., Lee, Y. H., Song, G. G., Sohn, J., Park‐Min, K., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001591 · Cited by 45 · see citing works
Yang, J., Ryu, Y. H., Yun, C., & Han, S. H. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0309206 · Cited by 41 · see citing works
C5aR1 interacts with TLR 2 in osteoblasts and stimulates the osteoclast‐inducing chemokine CXCL 10
Mödinger, Y., Rapp, A. E., Pázmándi, J., Vikman, A., Holzmann, K., Haffner‐Luntzer, M., Huber-Lang, M. S., & Ignatius, A. A. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13873 · Cited by 41 · cited 3× · see citing works
“7 cell line it was observed that the supernatants potentiated the osteoclastogenic effect of RANKL by a mechanism that could be inhibited by antibodies neutralizing CXCL10.”
BackgroundInfluentialCai, X., Xing, J., Long, C. L., Peng, Q., & Humphrey, M. B. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3205 · Cited by 33 · cited 1× · see citing works
“In vivo, DOK3 mice have reduced trabecular bonemass and increased number of TRAP osteoclasts (36).”
BackgroundVerdrengh, M., Bokarewa, M. I., Ohlsson, C., Stolina, M., & Tarkowski, A. (2009) · Bone · doi:10.1016/j.bone.2009.10.028 · Cited by 32 · see citing works
Amcheslavsky, A., Hemmi, H., Akira, S., & Bar-Shavit, Z. (2005) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.050515 · Cited by 31 · cited 1× · see citing works
“macrophages than those in osteoblasts (102).”
Verdrengh, M., Carlsten, H., Ohlsson, C., & Tarkowski, A. (2006) · Journal of Orthopaedic Research® · doi:10.1002/jor.20317 · Cited by 30 · cited 1× · see citing works
“Bone resorption due to excessive osteoclast formation is also observed in Staphylococcus aureus septic arthritis (11, 12), an uncommon, but not rare disease affecting 2–10 patients of 100,000 in the general population (13).”
BackgroundAppearance of osteoclasts by injections of lipopolysaccharides in rat periodontal tissue
Umezu, A., Kaneko, N., Toyama, Y., Watanabe, Y., & Itoh, H. (1989) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.1989.tb00886.x · Cited by 30 · see citing works
Regulation of Osteoclastogenesis by Integrated Signals From Toll‐Like Receptors
Krisher, T., & Bar‐Shavit, Z. (2014) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24891 · Cited by 29 · cited 2× · see citing works
“Thus, synergistic inhibitory effects on osteoclast formation have been observed when mouse macrophages have been treated with TLR3 together with TLR4, or with TLR4 together with TLR9 (86).”
BackgroundToll-Like Receptor 9 Ligand Blocks Osteoclast Differentiation Through Induction of Phosphatase
Amcheslavsky, A., & Bar‐Shavit, Z. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.070501 · Cited by 26 · cited 2× · see citing works
“This might be due to that the activation of ERK1/2 by CpG-ODN is transient, whereas RANKL causes a sustained activation of ERK1/2, a difference which is explained by the finding that CpG-ODN, but not RANKL, induces the expression of the phosphatase PP2A (88).”
BackgroundSerum amyloid A inhibits RANKL-induced osteoclast formation
Oh, E., Lee, H. Y., Kim, H. J., Park, Y. J., Seo, J. K., Park, J. S., & Bae, Y. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2015.83 · Cited by 18 · cited 1× · see citing works
“This protein also inhibits RANKL-stimulated osteoclast formation in mouse bone marrow macrophage (BMM) cultures (90).”
BackgroundToll-like receptor 7 regulates osteoclastogenesis in rheumatoid arthritis
Kim, K., Kim, B., Won, J., Lee, K., Kim, H., & Lee, S. (2019) · The Journal of Biochemistry · doi:10.1093/jb/mvz033 · Cited by 18 · cited 10× · see citing works
“Given the crucial role of these transcription factors for osteoclast formation, as demonstrated by the lack of osteoclasts and the osteopetrotic skeleton seen in mice with genetic deletion of Fos (77) orNfatc1 (78), it is apparent that this difference in signaling downstream RANK and TLR2 is the reason why TLR2 activa…”
BackgroundResultInfluentialHaptoglobin Acts as a TLR4 Ligand to Suppress Osteoclastogenesis via the TLR4–IFN-β Axis
Kwon, J.-O., Jin, W. J., Kim, B., Ha, H., Kim, H.-H., & Lee, Z. (2019) · Journal of Immunology · doi:10.4049/jimmunol.1800661 · Cited by 14 · see citing works
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Bone remodeling: an operational process ensuring survival and bone mechanical competence
Bolamperti, S., Villa, I., & Rubinacci, A. (2022) · Bone Research · doi:10.1038/s41413-022-00219-8 · Cited by 482 · see citing works
Inflammasomes in Alveolar Bone Loss
Li, Y., Ling, J., & Jiang, Q. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.691013 · Cited by 215 · see citing works
“TLR2, TLR4, and TLR9 activation arrest osteoclast differentiation in progenitors stimulated with RANKL and M-CSF and maintain the cells at the macrophage stage (88).”
BackgroundTargeting strategies for bone diseases: signaling pathways and clinical studies
Xu, H., Wang, W., Liu, X., Huang, W. H., Chen, Z., Xu, Y., Yang, H., Bai, J., & Geng, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01467-8 · Cited by 173 · see citing works
Gut microbiota and bone metabolism
Lu, L., Chen, X., Liu, Y., & Yu, X. (2021) · The FASEB Journal · doi:10.1096/fj.202100451r · Cited by 120 · see citing works
Topography-mediated immunomodulation in osseointegration; Ally or Enemy
Shirazi, S., Ravindran, S., & Cooper, L. F. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121903 · Cited by 104 · see citing works
Kim, H., Song, M., Gho, Y. S., Kim, H., & Choi, B. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12157 · Cited by 84 · see citing works
“F. alocis EVs induce osteoclastogenesis via TLR TLRs are involved in the recognition of various MAMPs and the intracellular signalling and are expressed by osteoclast progenitors (Souza & Lerner, 2019).”
Bastos, R., Oliveira, P. G., Gaspar, V. M., Mano, J. F., Coimbra, M. A., & Coelho, E. (2021) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2021.118826 · Cited by 75 · see citing works
Gaucher disease: Basic and translational science needs for more complete therapy and management
Grabowski, G. A., Antommaria, A. H. M., Kolodny, E. H., & Mistry, P. K. (2020) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2020.12.291 · Cited by 59 · see citing works
Microbiome’s role in musculoskeletal health through the gut-bone axis insights
Li, Z., Wang, Q., Huang, X., Wu, Y., & Shan, D. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2410478 · Cited by 58 · see citing works
“63 Although TLR5 is not directly expressed on osteoclasts, its activation on immune cells can indirectly affect osteoclastogenesis by influencing the secretion of cytokines that regulate bone resorption and formation.”
BackgroundThe production and application of bacterial exopolysaccharides as biomaterials for bone regeneration
Bagnol, R. A., Grijpma, D. W., Eglin, D., & Moriarty, T. F. (2022) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2022.119550 · Cited by 49 · see citing works
Wallimann, A., Hildebrand, M., Groeger, D., Stanić, B., Akdiş, C. A., Zeiter, S., Richards, R. G., Moriarty, T. F., O’Mahony, L., & Thompson, K. (2021) · Calcified Tissue International · doi:10.1007/s00223-020-00790-4 · Cited by 48 · see citing works
Ding, P., Tan, Q., Wei, Z., Chen, Q., Wang, C., Qi, L., Wen, L., Zhang, C., & Yao, C. (2022) · Bone Research · doi:10.1038/s41413-022-00210-3 · Cited by 47 · see citing works
“DISCUSSION TLRs are recognized as important links between bone and the immune system since the activation of TLRs in innate immune cells induces the release of proinflammatory cytokines that promote osteoclast differentiation.(66) Although numerous studies have focused on the effects of TLR activation on osteoclasts a…”
BackgroundKim, H., Song, M., Lim, Y., Jang, J. S., An, S., Kim, H., & Choi, B. (2022) · Scientific Reports · doi:10.1038/s41598-022-18412-4 · Cited by 45 · see citing works
Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns
Kwon, Y., Park, C. Y., Lee, J., Park, D. H., Jeong, S., Yun, C., Park, O.-J., & Han, S. H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115805 · Cited by 44 · see citing works
The osteoblast secretome in Staphylococcus aureus osteomyelitis
Granata, V., Possetti, V., Parente, R., Bottazzi, B., Inforzato, A., & Sobacchi, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1048505 · Cited by 44 · see citing works
“All TLRs but TLR2 and TLR4 are downregulated during osteoclast differentiation, and relative timing of TLR and RANKL/MCSF stimulation of osteoclast precursors elicit opposite effect on osteoclast formation (9).”
BackgroundInfluentialThe role of innate immunity in diabetic nephropathy and their therapeutic consequences
Yang, M., & Zhang, C. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.09.003 · Cited by 41 · see citing works
“Based on clinical evidence, TLR2 and TLR4 ligands such as endotoxins, HSP60, and HMGB1 are more abundant in patients with T1DM (Table 1) [37,46].”
BackgroundTLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging
Albuquerque‐Souza, E., Crump, K. E., Rattanaprukskul, K., Li, Y., Shelling, B., Xia, X., Jiang, M., & Sahingur, S. E. (2022) · Journal of Dental Research · doi:10.1177/00220345221110108 · Cited by 35 · see citing works
Roper, P., Shao, C., & Veis, D. (2020) · Cells · doi:10.3390/cells9102157 · Cited by 30 · see citing works
“Many bacteria produce lipoproteins and other products that bind pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) [10,11], some of which are present on the plasma membrane of OC lineage cells (Figure 1).”
BackgroundInfluentialThe Role of Toll-Like Receptors in Osteoclastogenesis
Yim, M. (2020) · Journal of Bone Metabolism · doi:10.11005/jbm.2020.27.4.227 · Cited by 28 · see citing works
“[42-47] Both positive and negative effects of TLRs on osteoclast differentiation have been reported in vitro.”
BackgroundOsteoclast Activation and Inflammatory Bone Diseases: Focusing on Receptors in Osteoclasts
Zhao, W., Li, J., Su, T., Wang, C., Fu, Y., Li, C., Hua, P., Liang, X., Zhu, Y., & Cui, H. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s507269 · Cited by 27 · see citing works
Dinesh, P., Kalaiselvan, S., Sujitha, S., & Rasool, M. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29757 · Cited by 26 · see citing works
“For the osteoclasts to thrive in the micro- environment, two essential extracellular secretions namely macrophage colony‐stimulating factor (M‐CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) are required (de Vries et al., 2019; Souza & Lerner, 2019).”
BackgroundWan, B., Xu, W., Chen, M., Sun, S., Jin, J., Lv, Y., Zhan, P., Zhu, S., Wang, X.-X., Lv, T., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.12.024 · Cited by 23 · see citing works
Karlis, G. D., Schöningh, E., Jansen, I. D. C., Schoenmaker, T., Hogervorst, J. M. A., van Veen, H. A., Moonen, C. G. J., Łagosz-Ćwik, K. B., Forouzanfar, T., & de Vries, T. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01693 · Cited by 22 · see citing works
“In the recent review of Souza and Lerner (62), it is also supported that activation of TLR agonists in different stages affects differently the maturation of the osteoclasts.”
BackgroundPTEN: an emerging target in rheumatoid arthritis?
Zhou, P., Meng, X., Nie, Z., Wang, H., Wang, K., Du, A., & Lei, Y. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01618-6 · Cited by 22 · see citing works
Phytocystatin CsinCPI-2 Reduces Osteoclastogenesis and Alveolar Bone Loss
Leguizamón, N. D. P., de Molon, R. S., Coletto-Nunes, G., Nogueira, A. V. B., Rocha, S. V., Neo-Justino, D. M., Soares‐Costa, A., Cerri, P. S., Lerner, U. H., de Souza, P. P. C., et al. (2021) · Journal of Dental Research · doi:10.1177/00220345211027811 · Cited by 20 · see citing works
Self-citationBiological Effects of β-Glucans on Osteoclastogenesis
Ariyoshi, W., Hara, S., Koga, A., Nagai‐Yoshioka, Y., & Yamasaki, R. (2021) · Molecules · doi:10.3390/molecules26071982 · Cited by 19 · see citing works
“TLR1-9 is expressed on osteoclast progenitors, and several ligands for TLRs have been shown to regulate osteoclastogenesis [64].”
BackgroundToll-Like Receptor Evolution: Does Temperature Matter?
Sousa, C., Fernandes, S. A., Cardoso, J. C. R., Wang, Y., Zhai, W., Guerreiro, P. M. M., Chen, L., Canário, A. V. M., & Power, D. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.812890 · Cited by 19 · see citing works
Madel, M., Halper, J., Ibáñez, L., Claire, L., Rouleau, M., Boutin, A., Mahler, A., Pontier-Bres, R., Ciucci, T., Topi, M., et al. (2023) · eLife · doi:10.7554/elife.82037 · Cited by 19 · see citing works
Park, S., Yoon, K., Hong, E., Kim, M. W., Kang, M. G., Mizuno, S., Kim, H. J., Lee, M.-J., Choi, H. J., Heo, J. S., et al. (2025) · Bone Research · doi:10.1038/s41413-025-00419-y · Cited by 17 · see citing works
miR-134-5p inhibits osteoclastogenesis through a novel miR-134-5p/Itgb1/MAPK pathway
Huang, M., Wang, Y., Wang, Z., Qin, Q., Zhang, H., Liu, S., Cui, J., Zhang, Y., Jiang, X., & Xu, L. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102116 · Cited by 17 · see citing works
“Their differentiation requires various factors, among which macrophage colonystimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) are prominent (11).”
BackgroundUse of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation
Khokhani, P., Rahmani, N. R., Kok, A., Öner, F. C., Alblas, J., Weinans, H., Kruyt, M. C., & Croes, M. (2021) · Materials · doi:10.3390/ma14051119 · Cited by 17 · see citing works
“While PRR activation and subsequent pro-inflammatory cytokine induction is known to mediate osteoclast formation through the NF-κB signaling pathway [43,44], it reportedly leads to varying outcomes depending on the maturation stage of the osteoclast precursor cell [49,50,56].”
BackgroundThe Pandemic That Has Forced Teachers to Go Online. Zooming in on Tips for Online Teaching
de Vries, T. J. (2021) · Frontiers in Education · doi:10.3389/feduc.2021.647445 · Cited by 16 · see citing works
“This year, I invited a friend from Brazil, who presented on his molecular cell biological work on infection models and bone degradation by osteoclasts (Souza and Lerner, 2019).”
BackgroundLactobacillus rhamnosus inhibits osteoclast differentiation by suppressing the TLR2 / NF‐κB pathway
Fu, J., Lü, J., Wu, L., Jiang, Y., Zhao, R., Du, J., Guo, L., Zhang, C., Xu, J., & Liu, Y. F. (2023) · Oral Diseases · doi:10.1111/odi.14712 · Cited by 15 · see citing works
RANK+TLR2+ myeloid subpopulation converts autoimmune to joint destruction in rheumatoid arthritis
Zhang, W., Noller, K., Crane, J. L., Wan, M., Wu, X., Cahan, P., & Cao, X. (2023) · eLife · doi:10.7554/elife.85553 · Cited by 15 · see citing works
“…that have been previously reported that showed that treatment with agonists for TLR2 increases osteoclast formation with significant bone loss ( Souza and Lerner, 2019 ; Elshabrawy et al., 2017 ), and that TRAP + preosteoclasts derived from TLR2 knockout mice do not differentiate into mature…”
Toll-like receptor 4 signaling in osteoblasts is required for load-induced bone formation in mice
Rajpar, I., Kumar, G., Fortina, P. M., & Tomlinson, R. E. (2023) · iScience · doi:10.1016/j.isci.2023.106304 · Cited by 13 · see citing works
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Staphylococci planktonic and biofilm environments differentially affect osteoclast formation
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“The effect of TLR activation on osteoclast formation is dependent on the commitment stage of the precursor cells (reviewed in [22]): Stimulation of uncommitted macrophages with TLR ligands and RANKL inhibits osteoclastogenesis [43] whereas TLR activation of RANKLprimed osteoclast progenitor cells increases osteoclast…”
BackgroundHengtrakool, P., Leearamwat, N., Sengprasert, P., Wongphoom, J., Chaichana, T., Taweevisit, M., Ngarmukos, S., Tanavalee, A., Palaga, T., & Reantragoon, R. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1326953 · Cited by 12 · see citing works
“IL-1 b and TNF a also directly induces osteoclast precursors to differentiate into mature osteoclasts (37).”
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“In particular, TLR2, and TLR4 are important in recognizing the periodontopathogenic component (9, 10).”
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“Activation of the MyD88-dependent pathway mainly leads to the production of proinflammatory cytokines, whereas the TRIF pathway triggers interferon production (Souza and Lerner, 2019).”
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“One of the possible reasons for this discrepancy may be due to different immunological properties of BMMs and committed osteoclast precursors (Souza & Lerner, 2019).”
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Histochemical assessment on osteoclasts in long bones of toll-like receptor 2 (TLR2) deficient mice
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Genome-Wide Scan Reveals Toll-Like Receptor Contraction Events in Oplegnathidae
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“TLR4 has also been reported to be involved in regulating the differentiation and cell fate determination of stem cells [2, 34].”
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“TLR5 is mainly expressed on immune cells, including macrophages and dendritic cells, which is crucial for regulating immune responses and is related to the control of bone homeostasis 76,77 .”
Osteogenic CpG Oligodeoxynucleotide, iSN40, Inhibits Osteoclastogenesis in a TLR9-Dependent Manner
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Editorial: Unveiling immunological mechanisms of periodontal diseases
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“Additionally, it was found that increased osteoclast activity in patients with TB spondylitis was activated via TLR-4 [19] .”
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“17 However, CD14-deficient OC differentiation was not inhibited in the presence of LPS, indicating that it is a required co-factor mediating the inhibitory effects of low levels of LPS.”
Systemic cachexia and muscle–bone crosstalk drive depression-related joint remodeling and pain
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“Similar to TLR signaling, the effect depends on the differentiation state: macrophages are more susceptible when activation coincides with early RANKL stimulation, whereas pre-committed osteoclast precursors are less affected [28, 31, 32].”
- Authors
- Souza, P. P. C., & Lerner, U. H.
- Affiliations
- University of Gothenburg (SE)
- Corresponding author
- Lerner, Ulf H.
- ORCID
- Lerner, Ulf H.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2019-07-17
- Volume
- 10
- Pages
- 1663-1663
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6652233
- OpenAlex
- W2959744610
- Cited by
- 67
- References
- 104
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 11 · 2020: 7 · 2019: 3
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Stiftelsen för Strategisk Forskning
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- osteoclast precursors, Toll-like receptors, osteoclastogenesis, macrophage colony-stimulating factor, RANKL, TLR2, TLR4, TLR5, TLR9, bone resorption, osteoblasts, bone loss, macrophage differentiation
- MeSH terms
- Animals, Bone Resorption, Cell Differentiation, Humans, Osteoblasts, Osteoclasts, Stem Cells, RANK Ligand
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