Abstract

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTHR1) is a G protein-coupled receptor that signals via multiple G proteins including Gsa. Mice expressing a constitutively active mutant PTHR1 exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsa in the osteoblast lineage. Postnatal removal of Gsa in the osteoblast lineage (P-GsaOsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 µg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-GsaOsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-GsaOsxKO mice. In mice that express a mutated PTHR1 that activates adenylyl cyclase and protein kinase A (PKA) via Gsa but not phospholipase C (PLC) via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that PLC activation is not required for increased bone turnover in response to PTH. Therefore while the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsa in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsa and Gq/11 act downstream of PTH on osteoblast differentiation.

View details for DOI 10.1074/jbc.M115.679753

View details for PubMedID 26598522