FLUORIDE EFFECTS ON OSTEOBLAST EXTRACELLULAR MATRIX

氟在骨质疏松症的治疗中被认为是有价值的 自1961年Rich和Ensink的研究以来，临床上，F被报告为 增加椎体骨密度，降低 脊椎骨折尽管据报道可以刺激成骨细胞功能， 在骨骼组织中，还已知其诱导类骨质增生和 矿化缺陷对这些事实的认识限制了其临床应用。 使用，因为担心在某些情况下会诱发骨软化， 患者和关于股骨骨折增加的矛盾数据。 F对骨小梁的这些明显不同的作用的基础 体积和骨基质合成仍然不确定。这是一个重要 问题，因为有兴趣在扩大临床使用的F在 治疗风湿性疾病。 通过组织形态计量学，已观察到F增加成骨细胞数量， 类骨质体积和松质骨体积。但成矿滞后时间 新的类骨质也增加了。据报道，在组织培养中， 刺激成骨细胞增殖和碱性磷酸酶产生。 在体外对成骨细胞代谢的其他影响已经被注意到，包括; cAMP和细胞间钙变化。然而，F对I型的影响 胶原代谢并没有被一致地观察到， 观察到体内类骨质形成增加。 我们推测氟诱导的类骨质增生和矿化 缺陷是F对成骨细胞定向的细胞外 基质（ECM）合成及其随后的矿化。我们将研究 使用明确的鸡成骨细胞形成矿化ECM 细胞培养模型我们将研究合成，加工和 成骨细胞特异性蛋白质在矿化ECM中的积累 长期暴露于F.从这个模型中获得的知识将 用于研究氟对培养的人成骨细胞的影响 从正常人和自闭症患者身上。增加对机制的了解 在体外的F作用应该导致更好地使用该代理作为一个 骨质疏松症的治疗方式。

Fluoride (F) has been considered of value in the therapy of osteoporosis since the studies of Rich and Ensink in 1961. Clinically, F is reported to increase vertebral bone mineral density and decrease the incidence of vertebral fractures. Although reported to stimulate osteoblast function in skeletal tissue, it is also known to induce hyperosteoidosis and a mineralization defect. Recognition of these facts has limited its clinical use because of concern about the induction of osteomalacia in certain patients and conflicting data regarding an increase in femoral fractures. The basis for these apparently contrasting effects of F on trabecular bone volume and bone matrix synthesis remains undefined. This is an important issue because of an interest in the expanded clinical use of F in the treatment of osteoporotic disorders. By histomorphometry, F has been observed to increase osteoblast number, osteoid volume and trabecular bone volume. However, mineralization lag time of new osteoid is also increased. In tissue culture F has been reported to stimulate osteoblast proliferation and alkaline phosphatase production. Other effects on osteoblast metabolism in vitro have been noted, including; cAMP and intercellular calcium alterations. However, F effects on type I collagen metabolism have not been consistently observed despite the observation of increased osteoid formation in vivo. We hypothesize that the F induced hyperosteroidosis and mineralization defect is a consequence of F effects on osteoblast-directed extracellular matrix (ECM) synthesis, and its subsequent mineralization. We will examine the formation of mineralizing ECM using a well defined, chicken osteoblast cell culture model. We will investigate the synthesis, processing and accumulation of osteoblast-specific proteins into a mineralizing ECM during chronic exposure to F. Knowledge gained from this model will then be applied to studies of the effect of F on cultured human osteoblast cells from normal and osteoporotic subjects. Increased knowledge of the mechanism of F action in vitro should lead to better use of the agent as a therapeutic modality in osteoporosis.