title: Osteoclast TGF-β Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation.
abstract: Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption. These processes become uncoupled with age, leading to increased risk for debilitating fractures. Therefore, understanding how osteoblasts are recruited to sites of resorption is vital to treating age-related bone loss. Osteoclasts release and activate TGF-β from the bone matrix. Here we show that osteoclast-specific inhibition of TGF-β receptor signaling in mice results in osteopenia due to reduced osteoblast numbers with no significant impact on osteoclast numbers or activity. TGF-β induced osteoclast expression of Wnt1, a protein crucial to normal bone formation, and this response was blocked by impaired TGF-β receptor signaling. Osteoclasts in aged murine bones had lower TGF-β signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGF-β-induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGF-β availability with age. Therefore, osteoclast responses to TGF-β are essential for coupling bone resorption to bone formation, and modulating this pathway may provide opportunities to treat age-related bone loss.
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Weivoda
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ruan
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Pederson
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hachfeld
authors.affiliation: Department of Medicine, Austin Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Davey
authors.affiliation: Department of Medicine, Austin Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Zajac
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.affiliation: Division of Endocrinology, Metabolism, Nutrition, and Diabetes, Mayo Clinic, Rochester, MN, USA.
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism* / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse
keywords: BONE REMODELING; COUPLING; OSTEOCLAST; TGF-β; WNT1