Role of matrix proteins in the local regulation of bone metabolism and its abonomalities in osteoporosis

点击翻译按钮获取中文摘要

1.Regulation of osteoblastic differentiation by cell-matrix interactions : Interaction of type I collagen (COL(I)) with alpha2beta1 integrin causes differentiation and transforming growth factor (TGF) -beta receptor down-regulation in osteoblastic cells. The TGF-beta receptor down-regulation enables cells to escape from the inhibition of differentiation by TGF-beta. To clarify how the cell-matrix interaction regulates these phenotypic changes, signaling pathways were examined in murine MC3T3-E1 cells. Attachment of cells to COL (I) stimulated tyrosine phosphorylation of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK), and enhanced MAPK activity. Inhibition of tyrosine kinase by herbimycin A,destruction of focal adhesion by cytochalasin D,or overexpression of antisense FAK mRNA prevented the activation of MAPK and the increase in alkaline phosphatase (ALP) activity. Transient expression of a MAPK-specific phosphatase, CL100, also suppressed the elevation of ALP a … More ctivity. In contrast, TGF-beta receptor down-regulation was not affected by CL100, but was abrogated by wortmannin, a phosphatidyl inositol (PL) -3 kinase inhibitor. These results demonstrate that COL (I) -alpha2beta1 integrin interaction facilitates differentiation via FAK-MAPK pathway, and down-regulates TGF-beta receptors via FAK-PI-3 kinase pathway. These signaling pathways may play an important role in the sequential differentiation of osteoblasts during bone formation.2.Impaired interleukin (IL) -11 actions in sensence-accelerated mice (SAM) : SAM shows reduced bone formation with lower bone mineral density than its normal counterpart. Bone marrow stromal cells (BMSC) from SAM contain less osteoprogenitor cells while exhibiting enhanced adipocytic differentiation, and the formation of both osteoblasts and osteoclasts is impaired in SAM.Addition of IL-11 to BMSC from SAM suppressed adipogenesis and restored osteoblast formation. The expression of IL-11 was reduced in BMSC from SAM mice, whereas no abnormality was found in IL-11 cDNA from SAM mice. These results suggest that an insufficient expression of IL-11 in BMSC causes the impairment of osteoblast and osteoclast formation in SAM mice. Less