Regulation of osteoblastic differentiation and its implication in involutional osteoporosis

骨基质蛋白对tgf - β在成骨细胞中的作用的调节我们证明了由成骨细胞合成的骨基质蛋白decorin与tgf - β结合并增强其与成骨细胞受体的结合，从而增强tgf - β的生物活性。因此，decorin不仅是骨基质的组成部分，而且可能参与tgf -刺激的骨形成。成骨细胞通过α - β - a1整合素与I型胶原（COL）的相互作用被证明是成骨细胞分化所必需的。COL与整合素的结合引起酪氨酸磷酸化，并激活局灶黏附激酶（FAK）和ERK，这是MAP激酶家族的成员。几种抑制FAK的抑制剂抑制胶原诱导的成骨细胞分化。此外，FAK表达的减少和FAK反义mRNA的稳定表达破坏了ERK的活性和成骨细胞的分化。由于蛋白质磷酸酶CL100的瞬时表达使ERK失活，从而阻止了分化，因此ERK可能直接参与了分化。这些观察结果表明，细胞-基质相互作用，特别是col -整合素相互作用，通过激活与整合素、FAK和ERK直接相关的信号级联，本质上参与了成骨细胞的分化。衰老加速小鼠（SAM）的骨髓细胞成骨分化是一种代谢性骨质疏松的小鼠模型。我们发现，与对照SAMR1小鼠相比，SAMP6小鼠骨髓基质细胞的成骨细胞发生受损。用白细胞介素(IL)-11治疗可恢复这种紊乱。我们进一步发现，IL-11在SAMP6骨髓细胞中的表达低于SAMR1，提示IL-11作用不足导致SAMP6成骨细胞生成受损。因此，像IL-11这样的细胞因子的作用降低在更年期骨质疏松的发病机制中有待进一步研究。少

Modulation of TGF-beta actions in osteoblasts by bone matrix proteinsWe demonstrated that decorin, a bone matrix protein synthesized by osteoblasts, binds TGF-beta and enhances the binding to its receptors on osteoblastic cells, resulting in the augmentation of bioactivity of TGF-beta. Thus, decorin is not only a component of bone matrix but may be involved in the bone formation that is stimulated by TGF-beta.Involvement of collagen-integrin interactions in osteoblastic differentiationInteractions of osteoblastic cells to type I collagen (COL) via alpha2beta1 integrin were shown to be required for osteoblastic differentiation. The binding of COL to the integrin provoked tyrosine phosphorylation and activation of focal adhesion kinase (FAK) and ERK,a member of MAP kinase family. Several inhibitors that inhibit FAK suppressed collagen-induced osteoblastic differentiation. Furthermore, decrease in FAK expression with the stable expression of antisense mRNA for FAK disrupted both ERK activ … More ation and osteoblastic differentiation. Because transient expression of protein phosphatase CL100 that inactivates ERK prevented the differentiation, the direct involvement of ERK was suggested. These observations indicate that cell-matrix interactions, especially COL-integrin interactions, are essentially involved in the osteoblastic differentiation via activations of signaling cascades directly associated with the integrin, FAK and ERK.Osteoblastic differentiation in bone marrow cells in advancing with ageP6 strain of senescence-accerelated mice (SAM) is a murine model of involutional osteoporosis. We showed that osteoblastogenesis of bone marrow stromal cells was impaired in SAMP6 mice compared with the control SAMR1 mice. Treatment with interleukin (IL)-11 could restore this disturbance. We further showed that IL-11 expression in bone marrow cells of SAMP6 was less than that of SAMR1, suggesting that insufficient IL-11 actions causes the impaired osteoblastogenesis in SAMP6. Thus, a decrease in actions of cytokines like IL-11 is further to be investigated for the pathogenesis of involutional osteoporosis. Less