Regulation of osteoblastic differentiation and its implication in involutional osteoporosis

骨基质蛋白对成骨细胞中TGF-β作用的调节我们证明，核心蛋白聚糖是一种由成骨细胞合成的骨基质蛋白，它与TGF-β结合，并增强与成骨细胞上其受体的结合，从而增强TGF-β的生物活性。因此，核心蛋白聚糖不仅是骨基质的组分，而且可能参与由TGF-β刺激的骨形成。成骨细胞分化中胶原-整合素相互作用的参与成骨细胞通过α 2 β 1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需的。COL与整合素的结合可引起酪氨酸磷酸化，激活粘着斑激酶（FAK）和MAP激酶家族的ERK。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反义mRNA的稳定表达导致FAK表达的减少， 关于我们 成骨细胞分化。由于蛋白磷酸酶CL 100的瞬时表达使ERK失活，阻止了分化，因此建议ERK直接参与。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，主要通过激活与整合素、FAK和ERK直接相关的信号级联反应参与成骨细胞分化。我们发现，与对照组SAMR 1小鼠相比，SAMP 6小鼠骨髓基质细胞的成骨细胞分化受损。白细胞介素（IL）-11治疗可以恢复这种障碍。我们进一步表明，IL-11在SAMP 6的骨髓细胞中的表达低于SAMR 1，表明IL-11作用不足导致SAMP 6中成骨细胞生成受损。因此，细胞因子如IL-11的作用的减少将进一步研究退化性骨质疏松症的发病机制。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