HEPATOCYTE GROWTH-FACTOR AND ITS ACTIONS IN GROWTH-PLATE CHONDROCYTES

Hepatocyte growth factor (HGF) has been implicated as a paracrine regu lator of organogenesis and repair in many tissues, Here we have studie d the expression and actions of HGF in intact rachitic rat growth plat e and derived cultures of proliferative zone chondrocytes. In vivo and in vitro chondrocytes express HGF mRNA; 1,25(OH)(2) has a three-fold maximal stimulatory effect, which can be blocked by H-7, an inhibitor of protein kinase C, Although HGF elaboration and action generally fol low a paracrine model, chondrocytes appear capable of both expressing and responding to HGF, mRNA encoding the HGF receptor (c-met) was dete cted in both growth cartilage and derived chondrocyte cultures. HGF ad dition to chondrocyte cultures increased collagen II mRNA and alkaline phosphatase enzymatic activity to degrees comparable to that observed for active vitamin D metabolites, Combining HGF and 1,25-D evoked a s ynergistic response (ninefold) of alkaline phosphatase activity, To as sess whether a similar stimulatory effect might be seen with bioactive peptides and HGF, we investigated the effect of HGF pretreatment on a cute responses of chondrocytes to synthetic human calcitonin, an anabo lic chondrocyte regulator whose skeletal action are mediated principal ly by cAMP elevation and subsequent protein kinase A activation, CT's maximal activation of protein kinase A was increased by prior HGF trea tment from 56% to 78%, In concert, our findings indicate that in addit ion to HGF's classical paracrine role during skeletal growth, this gro wth factor may modulate hormonal sensitivity of the chondrocyte during proliferation, differentiation, and/or apoptosis.