Marrow stromal cells and osteoclast precursors differentially contribute to TNF-α-induced osteoclastogenesis in vivo

Hideki Kitaura, Mark S. Sands, Kunihiko Aya, Ping Zhou, Teruhisa Hirayama, Brian Uthgenannt, Shi Wei, Sunao Takeshita, Deborah Veis Novack, Matthew J. Silva, Yousef Abu-Amer, F. Patrick Ross, Steven L. Teitelbaum

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132 Citations (Scopus)

Abstract

The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-κ (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-α-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-α. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-α treatment or whether the recipient animals possess TNF-α-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-α 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-α 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-α is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-α depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-α may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.

Original languageEnglish
Pages (from-to)4838-4846
Number of pages9
JournalJournal of Immunology
Volume173
Issue number8
Publication statusPublished - 2004 Oct 15
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    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. (2004). Marrow stromal cells and osteoclast precursors differentially contribute to TNF-α-induced osteoclastogenesis in vivo. Journal of Immunology, 173(8), 4838-4846.