Osteoclastogenic activity and RANKL expression are inhibited in osteoblastic cells expressing constitutively active Gα12 or constitutively active RhoA

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Abstract

12-RhoA signaling is a parathyroid hormone (PTH)-stimulated pathway that mediates effects in bone and may influence genetic susceptibility to osteoporosis. To further elucidate effects of the pathway in osteoblasts, UMR-106 osteoblastic cells were stably transfected with constitutively active (ca) Gα12 or caRhoA or dominant negative (dn) RhoA and co-cultured with RAW 264.7 cells to determine effects on hormone-stimulated osteoclastogenesis. Whereas PTH and calcitriol-stimulated osteoclastogenesis in co-cultures with UMR-106 cells expressing pcDNA or dominant negative RhoA, the osteoclastogenic effects of PTH and calcitriol were significantly attenuated when the UMR-106 cells expressed either caRhoA or caGα12. These inhibitory effects were partially reversed by the Rho kinase inhibitor Y27632. None of the constructs affected osteoclastogenesis in untreated co-cultures, and the constructs did not inhibit the osteoclastogenic responses to receptor activator of NFκB ligand (RANKL). To investigate the mechanism of the inhibitory effects of caGα 12 and caRhoA, expression of RANKL, osteoprotegerin (OPG), osteopontin (OPN), and intercellular adhesion molecule-1 (ICAM) in response to PTH or calcitriol was examined in the UMR-106 cells. In the cells expressing pcDNA or dnRhoA, PTH and calcitriol increased RANKL mRNA and decreased OPG mRNA, whereas these effects were absent in the cells expressing caGα 12 or caRhoA. Basal expression of RANKL and OPG was unaffected by the constructs. The results suggest that Gα12-RhoA signaling can inhibit hormone-stimulated osteoclastogenesis by effects on expression of RANKL and OPG. Since PTH can stimulate the Gα12-RhoA pathway, the current findings could represent a homeostatic mechanism for regulating osteoclastogenic action.

Original languageEnglish (US)
Pages (from-to)1531-1536
Number of pages6
JournalJournal of Cellular Biochemistry
Volume111
Issue number6
DOIs
StatePublished - Dec 15 2010

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Keywords

  • RhoA
  • calcitriol
  • osteoblast
  • osteoclastogenesis
  • parathyroid hormone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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