RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis

Bomi Lee, Urszula T. Iwaniec, Russell T. Turner, Yi Wei Lin, Bart L. Clarke, Anne Gingery, Li-Na Wei

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13 Scopus citations


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.

Original languageEnglish (US)
Article numbere90517
JournalJCI Insight
Issue number7
StatePublished - Apr 6 2017

Bibliographical note

Funding Information:
This work was supported by NIH grants DK54733, DK60521, and DK60521-12S1, the Dean’s Commitment and the Distinguished McKnight Professorship of the University of Minnesota (to L.N.W.), and NIH grant F32-AR063596, Mayo Clinic Center for Regenerative Medicine (to A.G.).

Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.


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