期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 202, 期 5, 页码 589-595出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050978
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资金
- NIAMS NIH HHS [AR38933, AR48231, P01 AR038933, AR46026, R01 AR049078, R01 AR048714, AR48714, P30 AR046026, R03 AR048231, AR49078] Funding Source: Medline
Osteoclasts are derived from myeloid lineage cells, and their differentiation is supported by various osteotropic factors, including the tumor necrosis factor (TNF) family member TNF-related activation-induced cytokine (TRANCE). Genetic deletion of TRANCE or its receptor, receptor activator of nuclear factor kappa B (RANK), results in severely osteopetrotic mice with no osteoclasts in their bones. TNF receptor-associated factor (TRAF) 6 is a key signaling adaptor for RANK, and its deficiency leads to similar osteopetrosis. Hence, the current paradigm holds that TRANCE-RANK interaction and subsequent signaling via TRAF6 are essential for the generation of functional osteoclasts. Surprisingly, we show that hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can become osteoclasts in vitro when they are stimulated with TNF-alpha in the presence of cofactors such as TGF-beta. We provide direct evidence against the current paradigm that the TRANCE-RANK-TRAF6 pathway is essential for osteoclast differentiation and suggest the potential existence of alternative routes for osteoclast differentiation.
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