TitleRIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis.
Publication TypeJournal Article
Year of Publication2017
AuthorsLee, B, Iwaniec, UT, Turner, RT, Lin, Y-W, Clarke, BL, Gingery, A, Wei, L-N
JournalJCI Insight
Volume2
Issue7
Paginatione90517
Date Published04/2017
ISSN2379-3708
Abstract
 

Osteolytic bone diseases, such as osteoporosis, are characterized by diminished bone quality and increased fracture risk. The therapeutic challenge remains to maintain bone homeostasis with a balance between osteoclast-mediated resorption and osteoblast-mediated formation. Osteoclasts are formed by the fusion of monocyte/macrophage-derived precursors. Here we report, to our knowledge for the first time, that receptor-interacting protein 140 (RIP140) expression in osteoclast precursors and its protein regulation are crucial for osteoclast differentiation, activity, and coupled bone formation. In mice, monocyte/macrophage-specific knockdown of RIP140 (mϕRIP140KD) resulted in a cancellous osteopenic phenotype with significantly increased bone resorption and reduced bone formation. Osteoclast precursors isolated from mϕRIP140KD mice had significantly increased differentiation potential. Furthermore, conditioned media from mϕRIP140KD primary osteoclast cultures significantly suppressed osteoblast differentiation. This suppressive activity was effectively and rapidly terminated by specific Syk-stimulated RIP140 protein degradation. Mechanistic analysis revealed that RIP140 functions primarily by inhibiting osteoclast differentiation through forming a transcription-suppressor complex with testicular receptor 4 (TR4) to repress osteoclastogenic genes. These data reveal that monocyte/macrophage RIP140/TR4 complexes may serve as a critical transcription regulatory complex maintaining homeostasis of osteoclast differentiation, activity, and coupling with osteoblast formation. Accordingly, we propose a potentially novel therapeutic strategy, specifically targeting osteoclast precursor RIP140 protein in osteolytic bone diseases.

DOI10.1172/jci.insight.90517
Alternate JournalJCI Insight
PubMed ID28405613
PubMed Central IDPMC5374065
Grant ListR01 DK054733 / DK / NIDDK NIH HHS / United States
R01 DK060521 / DK / NIDDK NIH HHS / United States