Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA.
J Bone Miner Res. 2010 Jul;25(7):1637-49. doi: 10.1002/jbmr.49.
Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone-bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone-related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease.
慢性甲状旁腺功能亢进症（HPT）是代谢性骨病的常见原因。这些研究调查了导致甲状旁腺激素（PTH）升高对骨骼产生有害作用的潜在细胞和分子机制。甲状旁腺功能亢进症患者的骨活检显示，甲状旁腺骨病与骨髓肥大细胞数量增加之间存在关联。因此，我们在慢性 HPT 的大鼠模型中评估了肥大细胞在甲状旁腺骨病发病机制中的作用。在大鼠中，成熟的肥大细胞优先位于正在进行骨转换的部位，并且在用 PTH 治疗后，骨-骨髓界面的肥大细胞数量大大增加。时程研究和使用甲状旁腺激素相关肽（PTHrP）以及血小板衍生生长因子-A（PDGF-A、trapidil）、kit（gleevec）和 PI3K（wortmannin）信号抑制剂的研究表明，成熟肥大细胞从骨髓向骨表面的重新分布先于并与纤维性骨炎相关，纤维性骨炎是甲状旁腺骨病的标志。重要的是，在骨髓中未观察到成熟的肥大细胞。反过来，小鼠对 PTH 诱导的骨髓纤维化的发展具有抗性。这些发现表明肥大细胞可能是治疗代谢性骨病的新靶点。
