Transforming growth factor-beta-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase-dependent pathway

Transforming growth factor-beta (TGF-beta) is a powerful modulator of bone metabolism, and both its anabolic and catabolic effects on bone have been d escribed. Here we have tested the hypothesis that TGF-beta -induced changes in osteoblast shape promote bone resorption by increasing the surface area of bone that is accessible to osteoclasts. The addition of TGF-beta1 to MC 3T3-E1 cells resulted in cytoskeletal reorganization, augmented expression of focal adhesion kinase, and cell elongation, accompanied by an increase i n the area of cell-free substratum. TGF-beta1 also triggered activation of Erk1/2 and p38 mitogen-activated protein (MAP) kinase. The p38 MAP kinase i nhibitor PD169316, but not an inhibitor of the Erk1/2 pathway, abrogated th e effect of TGF-beta1 on cell shape. The matrix metalloproteinase inhibitor GM6001 also interfered with osteoblast elongation. Treatment of MC3T3-E1 c ells seeded at confluence onto bone slices to mimic a bone lining cell laye r with TGF-beta1 also induced cell elongation and increased pit formation b y subsequently added osteoclasts. These effects were again blocked by PD169 316 and GM6001. We propose that this novel pathway regulating osteoblast mo rphology plays an important role in the catabolic effects of TGF-beta on bo ne metabolism.