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 trans duced by the pathways of adenylyl cyclase (AC)/protein kinase (PK) A a nd phospholipase C/PKC/Ca++. There is still uncertainty about the rela tive 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 proliferat ion in cultured mouse calvariae, In isolated osteoblasts, only PMA sti mulated proliferation, whereas AC/PKA agonists and PTH(1-34) inhibited it. As already known, PTH in the presence of supramaximal concentrati ons of transforming growth factor-beta (TGF-beta) stimulated osteoblas t 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 ca lvaria cell proliferation faintly in comparison with PTH(1-34); no eff ect was seen in osteoblasts, either with or without TGF-beta. Our stud y shows that the effects of PTH on proliferation can be mimicked by ag onists of the AC/cAMP pathway. Although PMA is indeed able to stimulat e 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.