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

骨骼是一个动态的器官，其中矿化的骨被破骨细胞持续地再吸收，并且新骨由成骨细胞形成。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节。牙周组织的慢性感染和绝经使这一过程失去平衡，并通过刺激白细胞介素-1（IL-1）和IL-6等因子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（transforming growth factor beta，TGF-β）成员激活素A可抑制佛波酯和脂多糖刺激的单核细胞产生IL-1β，并增强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活性。本研究通过检测TGF-β家族成员包括激活素A在破骨细胞形成中的作用，获得了以下有趣的结果：当小鼠骨髓细胞与骨基质细胞共培养时，TGF-β1、激活素A、BMP-2刺激维生素D3和IL-1α介导的破骨细胞形成; BMP-2促进破骨细胞形成似乎是通过破骨细胞分化因子（ODF）mRNA在骨基质细胞中的积累介导的;当骨髓细胞在M-CSF和ODF存在下培养时，激活素A强烈促进破骨细胞形成。这些结果表明，TGF-β家族成员在破骨细胞生成中起重要作用，激活素A抑制剂可用作骨质疏松症和牙周炎的治疗剂。

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.