Marrow Stromal Cells and Osteoclast Precursors Differentially Contribute to TNF-α-Induced Osteoclastogenesis In Vivo
Abstract
The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-kappaB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-alpha-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-alpha. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-alpha treatment or whether the recipient animals possess TNF-alpha-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-alpha requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-alpha increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-alpha is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-alpha depends upon responsive stromal cells. Alt…
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TNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors, with effects mediated by TNF-α receptors type 1 and type 2, the former being most effective in inducing differentiation of TRAP-positive multinucleated cells.
“TNF-α induces osteoclastogenesis in RANKL- and M-CSF-positive hematopoietic cell precursors [29,30], where its effects are mediated by TNF-α receptors type 1 (p55r) and type 2 (p75r), the former being the most effective in inducing the differentiation of TRAP-positive multinucleated cells [31].”
From Osteoclasts and Microgravity (2020) · cites this paper as [30]
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“In the context of inflammation, TNF- induces RANKL synthesis by marrow stromal cells (16), and RANKL prompts TNFexpression by osteoclast precursors (21).”
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Self-citationInflammatory osteolysis: A conspiracy against bone
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- Authors
- Kitaura, H., Sands, M. S., Aya, K., Zhou, P., Hirayama, T., Uthgenannt, B., Wei, S., Takeshita, S., Novack, D. V., Silva, M. J., Abu-Amer, Y., Ross, F. P., & Teitelbaum, S. L.
- Affiliations
- Washington University in St. Louis (US)
- Departments of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO 63110
- Orthopedic Surgery, Washington University School of Medicine , St. Louis, MO 63110
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-10
- Volume
- 173
- Issue
- 8
- Pages
- 4838-4846
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2168143492
- Cited by
- 190
- References
- 5
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 9 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 9 · 2012: 5
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56341, DK-57586, R01DK057586, P30DK056341)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-32788, R01AR048812, R01AR032788, AR-48853, R01AR048853, R01AR046852, AR46523, AR-48812, AR-46852)
- 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
- osteoclastogenesis, mesenchymal stem cells, osteoclast precursors, TNF-α, RANKL, RANK, TNF receptor, chimeric mice, T cell depletion, bone erosion, inflammatory arthritis, osteolysis
- MeSH terms
- Animals, Bone Marrow Cells, Carrier Proteins, Dose-Response Relationship, Drug, Female, Glycoproteins, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Inbred ICR, Osteoclasts, Stem Cells, Tumor Necrosis Factor-alpha, Stromal Cells, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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