title: Loss of Gsα early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors.
abstract: In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gs α activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gs α in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Sinha
authors.forename: Piia
authors.initials: P
authors.lastname: Aarnisalo
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Chubb
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ono
authors.forename: Keertik
authors.initials: K
authors.lastname: Fulzele
authors.forename: Martin
authors.initials: M
authors.lastname: Selig
authors.forename: Hamid
authors.initials: H
authors.lastname: Saeed
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.forename: Paola Divieti
authors.initials: PD
authors.lastname: Pajevic
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: ADIPOCYTES; GSA; MESENCHYMAL PROGENITORS; OSTEOBLASTS