Mechanism of action of parathyroid hormone-induced proteoglycan synthesis in the growth plate chondrocyte.
In the growth plate chondrocyte, parathyroid hormone (PTH) stimulates phosphoinositol 4,5 bisphosphate (PIP2) degradation, which results in the rapid production of inositol (1,4,5) triphosphate (IP3). IP3 induced the release of calcium from an intracellular store, which caused a rapid increase in the cytosolic ionized calcium concentration. Parathyroid hormone also induced a 30-50% increase in proteoglycan synthesis. Phorbol esters, which pharmacologically activate protein kinase C, resulted in a 70-80% increase in proteoglycan synthesis. Treatment of the chondrocytes with retinoic acid (0.2 microM) inhibited the parathyroid hormone and phorbol ester-induced increase in intracellular ionized calcium and the increase in proteoglycan synthesis. From this data we postulate that the stimulation of proteoglycan synthesis in growth plate chondrocytes by PTH is mediated by the breakdown of membrane phosphoinositides, which results in the production of IP3 and an increase in ionized intracellular calcium. It is suggested that the degradation of membrane phosphoinositides also results in production of diacylglycerol and, thereby, an activation of protein kinase C, which has a large stimulatory effect on proteoglycan synthesis. The increase in cytosolic calcium most likely acts synergetically with diacylglycerol to activate protein kinase C. Retinoic acid blocks the effect of PTH and phorbol ester-induced proteoglycan synthesis and may act through the inhibition of protein kinase C. The overall effect of PTH on the growth plate chondrocyte appears to be a stimulation of proteoglycan synthesis that is mediated by the degradation products of membrane phosphoinositides.
Iannotti
J P
JP
McKay Laboratory of Orthopaedic Research, University of Pennsylvania School of Medicine, Philadelphia 19104.
Brighton
C T
CT
Iannotti
V
V
Ohishi
T
T
D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis*
D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D010716:Phosphatidylinositols; D011509:Proteoglycans; D002118:Calcium