Alterations in bone fracture healing associated with TNFRSF signaling pathways
Open accessAbstract
Bone fracture healing is a complex process involving various signaling pathways. It remains an unsolved issue the fast and optimal management of complex or multiple fractures in the field of orthopedics and rehabilitation. Bone fracture healing is largely a four-stage process, including initial hematoma formation, intramembrane ossification, chondrogenesis, and endochondral ossification followed by further bone remodeling. Many studies have reported the involvement of immune cells and cytokines in fracture healing. On the other hand, the Tumor Necrosis Factor (TNF) family and TNF receptor superfamily (TNFRSF) play a pivotal role in many physiological processes. The functions of the TNF family and TNFRSF in immune processes, tissue homeostasis, and cell differentiation have been extensively studied by many groups, and treatments targeting specific TNFRSF members are in progress. In terms of bone fracture management, it has been discovered that several members of TNFRSF have very distinct functions in different stages of fracture healing, including TNFR1, TNFR2, and receptor activator of nuclear factor kappa-B (RANK) pathways. More specifically, TNFR1 is associated with osteoclastogenesis and TNFR2 is associated with osteogenic differentiation, while RANK is in association with bone remodeling. In this review, we will discuss and summarize the involvement of members of TNFRSF including TNFR1, TNFR2, and Receptor activator of nuclear factor kappa-B (RANK) pathways in different stages of fracture healing and bone remodeling and the current treatment trend involving TNFRSF agonists and antagonists.
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TNF-α's effects on bone may be related to regulation of RANKL.
“which may be related to the regulation of RANKL [86].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [86]
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Cites
An endotoxin-induced serum factor that causes necrosis of tumors
Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., & Williamson, B. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.9.3666 · Cited by 4,532 · see citing works
The TNF and TNF Receptor Superfamilies
Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00237-9 · Cited by 3,650 · see citing works
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Micheau, O., & Tschopp, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00521-x · Cited by 2,738 · see citing works
Hsu, H., Shu, H., Pan, M., & Goeddel, D. V. (1996) · Cell · doi:10.1016/s0092-8674(00)80984-8 · Cited by 1,998 · see citing works
Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems
Takayanagi, H. (2007) · Nature Reviews Immunology · doi:10.1038/nri2062 · Cited by 1,878 · see citing works
Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., & Werb, Z. (1998) · Cell · doi:10.1016/s0092-8674(00)81169-1 · Cited by 1,737 · see citing works
Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., & Teitelbaum, S. L. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11176 · Cited by 1,440 · see citing works
Wu, A.-M., Bisignano, C., James, S. L., Abady, G. G., Abedi, A., Abu-Gharbieh, E., Alhassan, R. K., Alipour, V., Arabloo, J., Asaad, M., et al. (2021) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00172-0 · Cited by 1,291 · see citing works
TNF? and the TNF receptor superfamily: Structure-function relationship(s)
Idriss, H. T., & Naismith, J. H. (2000) · Microscopy Research and Technique · doi:10.1002/1097-0029(20000801)50:3 · Cited by 1,175 · see citing works
Regulation of tumour necrosis factor signalling: live or let die
Brenner, D., Blaser, H., & Mak, T. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3834 · Cited by 998 · see citing works
Biology of RANK, RANKL, and osteoprotegerin
Boyce, B. F., & Xing, L. (2007) · Arthritis Research & Therapy · doi:10.1186/ar2165 · Cited by 962 · see citing works
Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment
Schett, G., & Gravallese, E. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.153 · Cited by 947 · see citing works
TNF and MAP kinase signalling pathways
Sabio, G., & Davis, R. J. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.02.009 · Cited by 705 · see citing works
Regulation of Fracture Repair by Growth Factors
Bolander, M. E. (1992) · Experimental Biology and Medicine · doi:10.3181/00379727-200-43410a · Cited by 637 · see citing works
Anti-TNF therapy: past, present and future
Monaco, C. G., Nanchahal, J., Taylor, P. C., & Feldmann, M. (2014) · International Immunology · doi:10.1093/intimm/dxu102 · Cited by 580 · see citing works
Raje, N. S., Terpos, E., Willenbacher, W., Shimizu, K., García‐Sánz, R., Durie, B. G. M., Legiec, W. M., Krejčí, M., Laribi, K., Zhu, L., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30072-x · Cited by 454 · see citing works
Gerstenfeld, L. C., Cho, T.-J., Kon, T., Aizawa, T., Tsay, A., Fitch, J. L., Barnes, G. B., Graves, D. T., & Einhorn, T. A. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.9.1584 · Cited by 434 · see citing works
Role of TNF–TNF Receptor 2 Signal in Regulatory T Cells and Its Therapeutic Implications
Yang, S., Wang, J., Brand, D. D., & Zheng, S. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00784 · Cited by 405 · see citing works
IL-17 as a future therapeutic target for rheumatoid arthritis
van den Berg, W. B., & Miossec, P. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.179 · Cited by 318 · see citing works
Exercise and bone health across the lifespan
Santos, L., Elliott-Sale, K. J., & Sale, C. (2017) · Biogerontology · doi:10.1007/s10522-017-9732-6 · Cited by 256 · see citing works
More to Life than NF-κB in TNFR1 Signaling
Ting, A. T., & Bertrand, M. J. M. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.06.002 · Cited by 254 · see citing works
Selective Targeting of TNF Receptors as a Novel Therapeutic Approach
Fischer, R., Kontermann, R. E., & Pfizenmaier, K. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00401 · Cited by 243 · see citing works
Gerstenfeld, L. C., Cho, T.-J., Kon, T., Aizawa, T., Cruceta, J., Graves, B., & Einhorn, T. A. (2001) · Cells Tissues Organs · doi:10.1159/000047893 · Cited by 236 · see citing works
TNF superfamily in inflammatory disease: translating basic insights
Croft, M., Duan, W., Choi, H., Eun, S.-Y., Madireddi, S., & Mehta, A. K. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.10.004 · Cited by 232 · see citing works
TNF receptors: signaling pathways and contribution to renal dysfunction
Al‐Lamki, R. S., & Mayadas, T. N. (2014) · Kidney International · doi:10.1038/ki.2014.285 · Cited by 215 · see citing works
Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target
Medler, J., & Wajant, H. (2019) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2019.1586886 · Cited by 177 · see citing works
Inflammation, mesenchymal stem cells and bone regeneration
Liu, H., Li, D., Zhang, Y., & Li, M. (2018) · Histochemistry and Cell Biology · doi:10.1007/s00418-018-1643-3 · Cited by 160 · see citing works
A TNF Receptor 2 Selective Agonist Rescues Human Neurons from Oxidative Stress-Induced Cell Death
Fischer, R., Maier, O., Siegemund, M., Wajant, H., Scheurich, P., & Pfizenmaier, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027621 · Cited by 130 · see citing works
Fischer, R., Wajant, H., Kontermann, R. E., Pfizenmaier, K., & Maier, O. (2013) · Glia · doi:10.1002/glia.22605 · Cited by 124 · see citing works
Granger, G. A., SHACKS, S. J., Williams, T. W., & Kolb, W. P. (1969) · Nature · doi:10.1038/2211155a0 · Cited by 109 · see citing works
Expression and function of TNF-family proteins and receptors in human osteoblasts>
Bu, R., Borysenko, C. W., Li, Y., Cao, L., Sabokbar, A., & Blair, H. C. (2003) · Bone · doi:10.1016/j.bone.2003.07.006 · Cited by 96 · see citing works
Multiple roles of tumor necrosis factor-alpha in fracture healing.
Karnes, J. M., Daffner, S., & Watkins, C. (2015) · Bone · doi:10.1016/j.bone.2015.05.001 · Cited by 82 · see citing works
Binding Studies of TNF Receptor Superfamily (TNFRSF) Receptors on Intact Cells
Lang, I., Füllsack, S., Wyzgol, A., Fick, A., Trebing, J., Arana, J. A. C., Schäfer, V., Weisenberger, D., & Wajant, H. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.683946 · Cited by 62 · see citing works
Effects of targeted therapies on bone in rheumatic and musculoskeletal diseases
Soos, B., Szentpetery, A., Raterman, H., Lems, W., Bhattoa, H., & Szekanecz, Z. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00764-w · Cited by 60 · see citing works
Fischer, R., Marsal, J., Guttà, C., Eisler, S. A., Peters, N., Bethea, J. R., Pfizenmaier, K., & Kontermann, R. E. (2017) · Scientific Reports · doi:10.1038/s41598-017-06993-4 · Cited by 53 · see citing works
David, J., & Schett, G. (2010) · Current directions in autoimmunity · doi:10.1159/000289202 · Cited by 49 · see citing works
Qi, Z., Liu, W., & Lu, J. (2016) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2016.05.010 · Cited by 47 · see citing works
Kontermann, R. E., Münkel, S., Neumeyer, J., Müller, D., Branschädel, M., Scheurich, P., & Pfizenmaier, K. (2008) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31816a88f9 · Cited by 43 · see citing works
Ota, N., Takaishi, H., Kosaki, N., Takito, J., Yoda, M., Tohmonda, T., Kimura, T., Okada, Y., Yasuda, H., Kawaguchi, H., et al. (2009) · Endocrinology · doi:10.1210/en.2009-0452 · Cited by 41 · see citing works
Ochi, H., Hara, Y., Tagawa, M., Shinomiya, K., & Asou, Y. (2009) · Journal of Orthopaedic Research · doi:10.1002/jor.21028 · Cited by 33 · see citing works
Wang, L., Zhang, J., Wang, C., Qi, Y., Du, M., Liu, W., Yang, C., & Yang, P. (2016) · Cell Proliferation · doi:10.1111/cpr.12311 · Cited by 29 · see citing works
Nagano, K., Alles, N., Mian, A. H., Shimoda, A., Morimoto, N., Tamura, Y., Shimokawa, H., Akiyoshi, K., Ohya, K., & Aoki, K. (2011) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-011-0270-z · Cited by 20 · see citing works
Zhang, Y., Yang, C., Ge, S., Wang, L., Zhang, J., & Yang, P. (2020) · BMC Molecular and Cell Biology · doi:10.1186/s12860-020-00273-2 · Cited by 20 · see citing works
Lukic, I., Grčević, D., Kovačić, N., Katavić, V., Ivčević, S., Kalajzić, I., & Marušić, A. (2004) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02680.x · Cited by 19 · see citing works
Improved monovalent TNF receptor 1-selective inhibitor with novel heterodimerizing Fc
Richter, F., Seifert, O., Herrmann, A., Pfizenmaier, K., & Kontermann, R. E. (2019) · mAbs · doi:10.1080/19420862.2019.1596512 · Cited by 18 · see citing works
TNFR2 signaling modulates immunity after allogeneic hematopoietic cell transplantation
Mancusi, A., Álvarez, M., Piccinelli, S., Velardi, A., & Pierini, A. (2019) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.05.001 · Cited by 15 · see citing works
Tharabenjasin, P., Pabalan, N., Jarjanazi, H., & Jinawath, N. (2021) · Osteoporosis International · doi:10.1007/s00198-021-06161-5 · Cited by 6 · see citing works
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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
“It was reported that TNF-α, such as IL-6, has a stimulating effect on bone resorption but an inhibitory effect on bone formation [84, 85], which may be related to the regulation of RANKL [86].”
BackgroundGhosh, S., Ghosh, R. B., Sawoo, R., Dutta, P., & Bishayi, B. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110766 · Cited by 10 · see citing works
Zhang, S., Chen, L., Zhang, C., Gong, C., He, X., Zhong, H., Liu, C., Cao, Z., Chen, W., Lin, N., et al. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5516 · Cited by 6 · see citing works
Bioglass-Reinforced Spongin-Like Collagen Scaffolds for Osteoporotic Bone Tissue Engineering
Cruz, M. D. A., Sousa, K. D. S. J., Avanzi, I. R., de Souza, A., Martignago, C. C. S., Bonifácio, M., Delpupo, F. V. B., Simões, M. C., Souza-Silva, L. C., Parisi, J. R., et al. (2025) · ACS Omega · doi:10.1021/acsomega.5c05580 · Cited by 3 · see citing works
Exploration of Multiscale Modeling on Functionally Graded Materials in Bone Remodeling: A Review
Gogate, P., Patil, S., & Dhatrak, P. N. (2025) · Journal of Bionic Engineering · doi:10.1007/s42235-025-00792-8 · Cited by 2 · see citing works
An experimental study on the effects of splenectomy on bone fracture healing
(2023) · Signa Vitae · doi:10.22514/sv.2023.067 · Cited by 2 · see citing works
Liu, R., Huang, Y., Jiang, M., Xu, F., Pei, Q., Ma, J., Li, Y., Shen, S., Zhang, B., Guo, X., et al. (2025) · Mechanobiology in Medicine · doi:10.1016/j.mbm.2025.100137 · Cited by 1 · see citing works
Chai, Y., Zhang, Y., Zhang, G., Song, S., Fu, W., Zhou, X., Zhang, Y., Lv, T., Chen, P., ZHANG, J., et al. (2026) · Frontiers in Veterinary Science · doi:10.3389/fvets.2026.1788225
Self-citationFracture healing: from molecular and cellular mechanisms to therapeutic strategies
Staubli, F., ten Ham, R. M. T., Bergsma, J. E., Gawlitta, D., & Man, K. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02967-z
- Authors
- Dong, Y., Zhou, H., Alhaskawi, A., Wang, Z., Lai, J., Abdullah Ezzi, S. H., Kota, V. G., Abdulla Hasan Abdulla, M. H., Sun, Z., & Lu, H.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
- Corresponding author
- Lu, Hui
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2022-10-17
- Volume
- 13
- Pages
- 905535-905535
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC9621617
- OpenAlex
- W4306392373
- Cited by
- 9
- References
- 47
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2
- FWCI
- 0.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of Zhejiang Province
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- fracture healing, TNF receptor superfamily, TNFR1, TNFR2, osteoclastogenesis, osteogenic differentiation, bone remodeling, endochondral ossification, intramembranous ossification, cytokines
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