title: A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.
abstract: The differentiation of osteoblasts from their precursors, mesenchymal stem cells, is an important component of bone homeostasis as well as fracture healing. The A2B adenosine receptor (A2BAR) is a Gα(s)/α(q)-protein-coupled receptor that signals via cAMP. cAMP-mediated signaling has been demonstrated to regulate the differentiation of mesenchymal stem cells (MSCs) into various skeletal tissue lineages. Here, we studied the role of this receptor in the differentiation of MSCs to osteoblasts. In vitro differentiation of bone marrow-derived MSCs from A2BAR KO mice resulted in lower expression of osteoblast differentiation transcription factors and the development of fewer mineralized nodules, as compared with WT mice. The mechanism of effect involves, at least partially, cAMP as indicated by experiments involving activation of the A2BAR or addition of a cAMP analog during differentiation. Intriguingly, in vivo, microcomputed tomography analysis of adult femurs showed lower bone density in A2BAR KO mice as compared with WT. Furthermore, A2BAR KO mice display a delay in normal fracture physiology with lower expression of osteoblast differentiation genes. Thus, our study identified the A2BAR as a new regulator of osteoblast differentiation, bone formation, and fracture repair.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Shannon H
authors.initials: SH
authors.lastname: Carroll
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Wigner
authors.forename: Nitin
authors.initials: N
authors.lastname: Kulkarni
authors.forename: Hillary
authors.initials: H
authors.lastname: Johnston-Cox
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D015519:Bone Density; D002113:Calcification, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D005269:Femur / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D043704:Receptor, Adenosine A2B; C493716:Runx2 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015124:8-Bromo Cyclic Adenosine Monophosphate