GPR35 regulates osteogenesis via the Wnt/GSK3β/β-catenin signaling pathway

Biochem Biophys Res Commun. 2021 Jun 4:556:171-178. doi: 10.1016/j.bbrc.2021.03.084. Epub 2021 Apr 8.

Abstract

It is well known that osteoporosis is a significant chronic disease with the increase of the aging population. Here, we report that expression of G protein-coupled receptor 35 (GPR35) in bone marrow mesenchymal stem cells (BMSCs) is suppressed in diagnosed osteoporosis patients and osteoporotic mice. The expression of GPR35 on BMSCs is enhanced during osteogenic differentiation. GPR35 knockout suppresses the proliferation and osteogenesis of BMSCs and deteriorates bone mass in both sham-treated and ovariectomized mice. Moreover, GPR35 deficiency reduces β-catenin activity in BMSCs. In contrast, the overexpression of GPR35 contributes to these processes in BMSCs. Finally, using zaprinast, a synthetic GPR35 agonist, we show that zaprinast rescues OVX-induced bone loss and promotes bone generation in mice. Thus, GPR35 may as a new target and its agonist zaprinast may serve as a novel treatment for osteoporosis.

Keywords: GPR35; GSK3β; Osteogenesis; Osteoporosis; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone Density / genetics
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Cell Proliferation
  • Female
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Humans
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Organ Size / drug effects
  • Organ Size / genetics
  • Osteogenesis*
  • Osteoporosis, Postmenopausal / drug therapy
  • Osteoporosis, Postmenopausal / prevention & control
  • Ovariectomy
  • Purinones / pharmacology
  • Purinones / therapeutic use
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism*

Substances

  • GPR35 protein, human
  • GPR35 protein, mouse
  • Purinones
  • Receptors, G-Protein-Coupled
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • zaprinast