Regulation of osteoblastic differentiation and its implication in involutional osteoporosis

骨基质蛋白对成骨细胞中转化生长因子-β作用的调节我们证明了成骨细胞合成的骨基质蛋白核心蛋白核心蛋白能与转化生长因子-β结合，并增强其与成骨细胞上受体的结合，从而增强转化生长因子-β的生物活性。因此，核心蛋白聚糖不仅是骨基质的一种成分，而且可能参与转化生长因子-β刺激的骨形成。成骨细胞分化过程中胶原-整合素相互作用的进展成骨细胞与I型胶原(Col)的相互作用是成骨细胞分化所必需的。Col与整合素结合可引起粘着斑激酶(FAK)和MAP激酶家族成员ERK的酪氨酸磷酸化和活化。几种抑制FAK的抑制剂可抑制胶原诱导的成骨细胞分化。此外，在FAK反义基因稳定表达的同时，FAK表达的减少也破坏了两种ERK激活的…更多的分化和成骨分化。由于瞬时表达的蛋白磷酸酶CL100使ERK失活，阻止了分化，因此ERK被认为是直接参与的。这些观察表明，细胞与基质的相互作用，尤其是Col与整合素的相互作用，通过激活与整合素、FAK和ERK直接相关的信号级联反应，本质上参与了成骨细胞的分化。衰老加速相关小鼠(SAM)P6品系的骨髓细胞成骨分化是一种进行性骨质疏松的小鼠模型。我们发现，与对照SAMR1小鼠相比，SAMP6小鼠的骨髓基质细胞成骨细胞的形成受到了损害。用白介素11治疗可以恢复这种紊乱。我们进一步发现SAMP6的骨髓细胞中IL-11的表达低于SAMR1，提示IL-11的作用不足导致了SAMP6的成骨细胞分化障碍。因此，在退化性骨质疏松症的发病机制中，IL-11等细胞因子的作用减少有待进一步研究。较少

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