Effects of parathyroid hormone and agonists of the adenylyl cyclase and protein kinase C pathways on bone cell proliferation.

The anabolic effect of parathyroid hormone (PTH) on bone is partly due to a stimulation of osteoblast proliferation. The PTH signal is transduced by the pathways of adenylyl cyclase (AC)/protein kinase (PK) A and phospholipase C/PKC/Ca++. There is still uncertainty about the relative contribution of the two pathways to the proliferative effects of the hormone. In our study, PTH(1-34), AC/PKA agonists, and phorbol 12-myristate-13-acetate (PMA, a PKC activator) stimulated cell proliferation in cultured mouse calvariae. In isolated osteoblasts, only PMA stimulated proliferation, whereas AC/PKA agonists and PTH(1-34) inhibited it. As already known, PTH in the presence of supramaximal concentrations of transforming growth factor-beta (TGF-beta) stimulated osteoblast growth; under these same conditions, AC/PKA agonists reproduced the stimulatory effect of PTH(1-34), whereas PMA became inhibitory. PTH(1-31), which stimulates AC without affecting PKC, acted similarly to the fully active PTH(1-34) in both calvaria and isolated osteoblasts. On the contrary, midregion fragments that activate only PKC stimulated calvaria cell proliferation faintly in comparison with PTH(1-34); no effect was seen in osteoblasts, either with or without TGF-beta. Our study shows that the effects of PTH on proliferation can be mimicked by agonists of the AC/cAMP pathway. Although PMA is indeed able to stimulate cell growth in tissue explants, its effects on isolated osteoblasts markedly diverge from those of PTH. We conclude that activation of the AC/PKA pathway is the main component of the proliferative effects of PTH.