Gimble J M, Morgan C, Kelly K, Wu X, Dandapani V, Wang C S, Rosen V
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
J Cell Biochem. 1995 Jul;58(3):393-402. doi: 10.1002/jcb.240580312.
The bone morphogenetic proteins were originally identified based on their ability to induce ectopic bone formation in vivo and have since been identified as members of the transforming growth factor-beta gene superfamily. It has been well established that the bone morphogenetic cytokines enhance osteogenic activity in bone marrow stromal cells in vitro. Recent reports have described how bone morphogenetic proteins inhibited myogenic differentiation of bone marrow stromal cells in vitro. In vivo, bone marrow stromal cells differentiate along the related adipogenic pathway with advancing age. The current work reports the inhibitory effects of the bone morphorphogenetic proteins on adipogenesis in a multipotent murine bone marrow stromal cell line, BMS2. When exposed to bone morphogenetic protein-2, the pre-adipocyte BMS2 cells exhibited the expected induction of the osteogenic-related enzyme, alkaline phosphatase. Following induction of the BMS2 cells with adipogenic agonists, adipocyte differentiation was assessed by morphologic, enzymatic, and mRNA markers. Flow cytometric analysis combined with staining by the lipophilic fluorescent dye, Nile red, was used to quantitate the extent of lipid accumulation within the BMS2 cells. By this morphologic criteria, the bone morphogenetic proteins inhibited adipogenesis at concentrations of 50 to 500 ng/ml. This correlated with decreased levels of adipocyte specific enzymes and mRNAs. The BMS2 pre-adipocytes constitutively expressed mRNA encoding bone morphogenetic protein-4 and this was inhibited by adipogenic agonists. Together, these findings demonstrate that bone morphogenetic proteins act as adipogenic antagonists. This supports the hypothesis that adipogenesis and osteogenesis in the bone marrow microenvironment are reciprocally regulated.
骨形态发生蛋白最初是根据其在体内诱导异位骨形成的能力而被鉴定出来的，此后被确定为转化生长因子-β基因超家族的成员。众所周知，骨形态发生细胞因子在体外可增强骨髓基质细胞的成骨活性。最近的报道描述了骨形态发生蛋白如何在体外抑制骨髓基质细胞的肌源性分化。在体内，随着年龄的增长，骨髓基质细胞沿相关的脂肪生成途径分化。目前的研究报告了骨形态发生蛋白对多能小鼠骨髓基质细胞系BMS2脂肪生成的抑制作用。当暴露于骨形态发生蛋白-2时，前脂肪细胞BMS2细胞表现出预期的成骨相关酶碱性磷酸酶的诱导。在用脂肪生成激动剂诱导BMS2细胞后，通过形态学、酶学和mRNA标记物评估脂肪细胞分化。流式细胞术分析结合亲脂性荧光染料尼罗红染色，用于定量BMS2细胞内脂质积累的程度。根据这种形态学标准，骨形态发生蛋白在50至500 ng/ml的浓度下抑制脂肪生成。这与脂肪细胞特异性酶和mRNA水平的降低相关。BMS2前脂肪细胞组成性表达编码骨形态发生蛋白-4的mRNA，而成脂激动剂可抑制这种表达。总之，这些发现表明骨形态发生蛋白可作为脂肪生成的拮抗剂。这支持了骨髓微环境中脂肪生成和成骨相互调节的假说。
