FLUORIDE EFFECTS ON OSTEOBLAST EXTRACELLULAR MATRIX

氟被认为在骨质疏松症的治疗中有价值 自1961年里奇和恩辛克的研究以来。临床上，F被报告为 增加椎体骨密度，降低骨质疏松症发生率 脊椎骨折。虽然报道有刺激成骨细胞功能的作用 骨骼组织，也是已知的诱导骨样增多症和一种 矿化缺陷。对这些事实的认识限制了它的临床应用 使用是因为担心在某些情况下会诱发骨软化症 患者和关于股骨骨折增加的相互矛盾的数据。 氟对骨小梁的这些明显反差作用的基础 体积和骨基质合成仍未确定。这是一个重要的 因为有兴趣扩大F在临床上的应用 骨质疏松症的治疗。 通过组织形态计量学观察到，F可以增加成骨细胞的数量， 骨样体积和骨小梁体积。然而，成矿滞后时间 新骨样物质的数量也增加了。在组织培养中，F已被报道为 刺激成骨细胞的增殖和碱性磷酸酶的产生。 在体外对成骨细胞代谢的其他影响也被注意到，包括； CAMP和细胞内钙离子改变。然而，F对I型的影响 胶原蛋白代谢并没有被一致地观察到，尽管 体内类骨形成增多的观察。 我们推测氟引起类固醇过多和矿化 缺陷是F对成骨细胞定向细胞外的影响的结果 基质(ECM)合成及其后续成矿作用。我们将研究 鸡成骨细胞形成矿化细胞外基质的研究 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在矿化细胞外基质中的积聚 长期接触F。从这个模型中获得的知识将是 氟对培养人成骨细胞影响的研究 来自正常的和骨质疏松的受试者。增加了对机制的了解 F在体外的作用应导致更好地将该试剂用作 骨质疏松的治疗方式。

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.