期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 115, 期 10, 页码 2742-2751出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI24921
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资金
- NIAMS NIH HHS [AR48853, AR46523, AR32788, AR46852, R01 AR048853, R01 AR032788, AR48812, R37 AR046523, R01 AR046852, R01 AR048812, R01 AR046523] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056341, DK-56341] Funding Source: Medline
TNF receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-KB (RANK). This event is central to normal osteoclastogenesis. We discovered that TRAF6 also interacts with FHL2 (four and a half LIM domain 2), a LIM domain-only protein that functions as a transcriptional coactivator or corepressor in a cell-type-specific manner. FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro. FHL2 inhibits TRAF6-induced NF-KB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6-mediated RANK signaling, TRAF6/RANK association is enhanced in FHL2(-/-) osteoclasts. FHL2 overexpression delays RANK ligand-induced (RANKL-induced) osteoclast formation and cytoskeletal organization. Interestingly, osteoclast-residing FHL2 is not detectable in naive wild-type mice, in vivo, but is abundant in those treated with RANKL and following induction of inflammatory arthritis. Reflecting increased RANKL sensitivity, osteoclasts generated from FHL2(-/-) mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts. As a consequence, FHL2(-/-) osteoclasts are hyperresorptive, and mice lacking the protein undergo enhanced RANKL and inflammatory arthritis-stimulated bone loss. FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling.
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