Immunosuppressant rapamycin inhibits protein kinase C alpha and p38 mitogen-activated protein kinase leading to the inhibition of chondrogenesis

Immunosuppressants are now known to modulate bone metabolism, including bon e formation and resorption. Because cartilage, formed by differentiated cho ndrocytes, serves as a template for endochondral bone formation, we examine d the effects of the immunosuppressant rapamycin on the chondrogenesis of m esenchymal cells and on the cell signaling that is required for chondrogene sis, such as protein kinase C, extracellular signal-regulated kinase-1 (ERK -1), and p38 mitogen-activated protein (MAP) kinase pathways. Rapamycin inh ibited the expression of type II collagen and the accumulation of sulfate g lycosaminoglycan, indicating inhibition of the chondrogenesis of mesenchyma l cells. Rapamycin treatment did not affect precartilage condensation, but it prevented cartilage nodule formation. Exposure of chondrifying mesenchym al cells to rapamycin blocked activation of the protein kinase C alpha and p38 MAP kinase, but had no discernible effect on ERK-1 signaling. Selective inhibition of PKC alpha or p38 MAP kinase activity, which is dramatically increased during chondrogenesis, with specific inhibitors in the absence of rapamycin blocked the chondrogenic differentiation of mesenchymal cells. T aken together, our data indicate that the immunosuppressant rapamycin inhib its the chondrogenesis of mesenchymal cells at the post-precartilage conden sation stage by modulating signaling pathways including those of PKC alpha and p38 MAP kinase. (C) 2001 Elsevier Science B.V. All rights reserved.