ECTS Abstracts (2015) 1 P196

Osteoblast-Specific Overexpression of G[alpha]11 Protein Promotes Osteoclastogenesis and Leads to Enhanced Responses to Antiresorptive Therapy

Ariana dela Cruz1,2, Lauren S Whyte1, Marc Grynpas2 & Jane Mitchell1

1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada, 2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.

Background: Gα11 is a member of the Gq protein family that mediates phospholipase C-dependent signalling downstream of G protein-coupled receptors. We previously demonstrated that dexamethasone increases Gα11 expression in osteoblasts and can enhance parathyroid hormone signalling through the phospholipase C pathway. Using transgenic mice that overexpress Gα11 in osteoblasts (G11-Tg) we showed that G11-Tg mice were osteopenic with a greater susceptibility to fracture as a result of reduced trabecular bone formation rate and increased osteoclast numbers and occupation surfaces. G11-Tg BMSC cultures had increased expression of osteoclast induction genes, M-csf and Rankl (Bone 2014 59:211). Our current study aims to investigate if Gα11 overexpression induces osteoclastogenesis and bone resorption in vitro, and the effects on responses to antiresorptive therapy in vivo.

Methods: BMSCs from WT and G11-Tg mice were co-cultured with WT spleen cells on cell culture plates or dentin discs in the presence of 1α,25-dihydroxyvitamin D3 to induce osteoclast differentiation. Osteoclastogenesis was evaluated with TRAP staining and measurement of resorption pits. To determine how G11-Tg mice respond to antiresorptive therapy, 8-week-old mice were treated with pamidronate (3 mg/kg weekly) or vehicle control. After 6 weeks of treatment, bone phenotypes were assessed by DEXA, microCT and histomorphometry.

Results: BMSC-osteoclast co-cultures derived from G11-Tg mice showed a significant increase in osteoclast number and size. Pamidronate treatment rescued the osteopenic phenotype of G11-Tg mice by returning femoral and L6 vertebral BMD to WT basal levels. Pamidronate had no effect on WT BMD. Histomorphometry of proximal tibial metaphyses showed significant improvement in trabecular bone volume in G11-Tg mice compared with WT.

Discussion: Our data suggest that osteoblast-specific overexpression of Gα11 promotes osteoclastogenesis in the local bone environment and that osteoclasts are key mediators of trabecular bone loss in G11-Tg mice. We are currently elucidating how Gα11 overexpression affects bone formation with anabolic therapies.

Disclosure: The authors declared no competing interests. This work was supported by the Canadian Institutes of Health Research.

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