title: RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis.
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.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Bomi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Skeletal Biology Laboratory, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Urszula T
authors.initials: UT
authors.lastname: Iwaniec
authors.affiliation: Skeletal Biology Laboratory, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Turner
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Clarke
authors.affiliation: Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Gingery
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006706:Homeostasis; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078723:Nuclear Receptor Interacting Protein 1 / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*
chemical_list: C490514:Nr2c2 protein, mouse; C000627128:Nrip1 protein, mouse; D000078723:Nuclear Receptor Interacting Protein 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone