Yamamoto T, Ozono K, Kasayama S, Yoh K, Hiroshima K, Takagi M, Matsumoto S, Michigami T, Yamaoka K, Kishimoto T, Okada S
Department of Pediatrics, Faculty of Medicine, Osaka University, Japan.
J Clin Invest. 1996 Jul 1;98(1):30-5. doi: 10.1172/JCI118773.
McCune-Albright syndrome (MAS) is characterized by café-au-lait spot, multiple endocrine hyperfunction, and polyostotic fibrous dysplasia. A somatic point mutation of Gsalpha protein was reported to decrease GTPase activity, leading to increase in the GSalpha-associated hormone actions via cAMP. IL-6 is known to stimulate osteoclast formation and in the IL-6 promoter, a cAMP responsive element has been identified. In this paper, we investigated the role of IL-6 in the bone lesions of MAS, using the isolated fibrous cells from the polyostotic fibrous dysplasia tissues in bones of the two patients with MAS. Bone biopsy specimen revealed the increased osteoclast in number. In both patients, a GSalpha mutation (Arg201 -> His) was identified in the cultured fibrous cells. Intracellular cAMP content and IL-6 secretion by the patient cells were increased. Rp-8Br-cAMP significantly inhibited IL-6 production in the patient cells, while it had no effect on normal control. The addition of dibutyryl cAMP significantly increased the synthesis of IL-6 in normal control cells. In contrast, no effect of dibutyryl cAMP on IL-6 synthesis was observed in the cells from one of the MAS patients. These data suggest that IL-6 is, at least, one of the downstream effectors of cAMP and that the increased IL-6 synthesis has a pathogenic role in the bone lesions of MAS patients via increasing the number of osteoclasts. These results may provide a new strategy for the therapy of MAS patients.
McCune - Albright综合征（MAS）的特征为咖啡斑、多种内分泌功能亢进和多骨型纤维性发育异常。据报道，Gsα蛋白的体细胞点突变会降低GTP酶活性，导致通过cAMP的Gsα相关激素作用增加。已知白细胞介素-6（IL-6）可刺激破骨细胞形成，并且在IL-6启动子中已鉴定出一个cAMP反应元件。在本文中，我们使用从两名MAS患者骨骼中的多骨型纤维性发育异常组织分离出的纤维细胞，研究了IL-6在MAS骨病变中的作用。骨活检标本显示破骨细胞数量增加。在两名患者的培养纤维细胞中均鉴定出Gsα突变（Arg201 -> His）。患者细胞的细胞内cAMP含量和IL-6分泌增加。Rp - 8Br - cAMP显著抑制患者细胞中IL-6的产生，而对正常对照无影响。加入二丁酰cAMP可显著增加正常对照细胞中IL-6的合成。相反，在一名MAS患者的细胞中未观察到二丁酰cAMP对IL-6合成有影响。这些数据表明，IL-6至少是cAMP的下游效应器之一，并且IL-6合成增加通过增加破骨细胞数量在MAS患者的骨病变中起致病作用。这些结果可能为MAS患者的治疗提供新策略。
