The effect of activin A, an antagonist of IL-1 and IL-6, on osteoclast formation.

骨骼是一个动态器官，破骨细胞不断吸收矿化骨，成骨细胞形成新骨。这一过程被称为骨重建，通常在维持正常骨量的情况下受到高度调控。牙周组织的慢性感染和更年期会使这一过程失去平衡，并通过刺激白介素1(IL-1)和白介素6(IL-6)的产生来增强骨吸收。我们前期的研究表明，转化生长因子-β(TGFR-β)家族成员激活素A能抑制佛波酯和脂多糖刺激的单核细胞产生IL-1β，促进IL-1受体拮抗剂的分泌。激活素-A还抑制IL-6在各种类型细胞中的生物学活性。在本研究中，我们研究了包括激活素-A在内的转化生长因子-β家族成员在破骨细胞形成中的作用，并获得了有趣的结果：当小鼠骨髓细胞与骨基质细胞共同培养时，所有受试的转化生长因子-β家族成员(转化生长因子-β1，激活素-A，骨形态发生蛋白-2)都刺激维生素D3和IL-1α介导的破骨细胞形成；骨形态发生蛋白-2促进破骨细胞的形成似乎是通过在骨髓细胞中积聚破骨细胞分化因子来实现的；当骨髓细胞在M-β和骨形态发生因子的存在下培养时，激活素-A强烈促进破骨细胞的形成。这些结果表明，转化生长因子-β家族成员在破骨细胞形成中起重要作用，激活素-A的抑制剂可以作为骨质疏松和牙周炎的治疗药物。

The skeleton is a dynamic organ in which mineralized bone is continuously resorbed by osteoclasts, and new bone is formed by osteoblasts. This process, known as bone remodeling, is normally highly regulated with maintenance of a normal amount of bone. Chronic infection of the periodontal tissue and menopause put the process out of balance and enhance bone resorption by stimulating production of factors such as interleukin-1 (IL-1) and IL-6. Our previous study demonstrated that activin A, a member of transforming growth factor beta (TGF-β), inhibited the production of IL-1β and enhanced secretion of IL-1 receptor antagonist in monocytic cells stimulated by phorbol ester and lipopolysaccharide. Activin-A also inhibits the biological activities of IL-6 in various types of cells. In this study, we examined the role of TGF-β family members including activin-A in the osteoclast formation and obtained interesting results as follows : when mouse bone marrow cells were co-cultured with bone stromal cells, all the TGF-β family members tested (TGF-β1, activin-A, BMP-2) stimulated vitamin D3- and IL-1α-mediated osteoclast formation ; enhancement of osteoclast formation by BMP-2 appeared to be mediated through accumulation of osteoclast differentiation factor (ODF) mRNA in bone stromal cells ; when bone marrow cells were cultured in the presence of M-CSF and ODF, activin-A strongly enhanced osteoclast formation. These results suggest that TGF-β family members play an important role in osteoclastogenesis and that inhibitors of activin-A can be used as a therapeutic agent of osteoporosis and periodontitis.