Although transforming growth factor (TGF)- enhances bone formation, it inhibits the differentiation of osteoblasts. To clarify the regulatory mechanism of osteoblastic differentiation and TGF- actions, the relationship among differentiation, TGF- actions, and matrix protein synthesis was examined using murine osteoblast-like MC3T3-E1 cells. Alkaline phosphatase (ALP) activity continued to increase during long-term cultures, and the increase was closely associated with a reduction in cell surface TGF- receptors competent to bind TGF-. Both the stimulation of proteoglycan synthesis and the inhibition of ALP activity by TGF- were also suppressed. Collagen synthesis inhibitors and an anti-21 integrin blocking antibody blocked the changes in ALP activity and TGF- receptors, and a DGEA peptide that interferes binding of collagen to 21 integrin also blocked the increase in ALP activity. Furthermore, when MC3T3-E1 cells were cultured on extracellular matrix layers obtained from these cells, all the differentiation-associated changes could be observed without collagen production, and the extracellular matrix-induced differentiation was also blocked by an anti-21 integrin antibody. These results demonstrate that the interaction of cell surface 21 integrin with matrix collagen synthesized by osteoblasts themselves is involved in the osteoblastic differentiation and the reduction in cell surface receptors and actions of TGF-. It is suggested that matrix collagen synthesized under the stimulation by TGF- plays an important role in the regulation of osteoblastic differentiation and TGF- actions by differentiation-associated down-regulation of TGF- receptors.

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