Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells
Role of the cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells
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DOI：
10.1359/jbmr.2002.17.11.1997
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发表时间：
2002-11-01
影响因子：
6.2
通讯作者：
Demer, LL
中科院分区：
文献类型：
--
作者：
Parhami, F;Mody, N;Demer, LL
胆固醇是调节细胞分化和功能的重要分子。尽管脂质可能参与调节成骨细胞，但胆固醇在这一过程中的作用尚不明确。在这项研究中，我们研究了细胞胆固醇生物合成途径在骨髓基质细胞（MSCs）成骨分化中的作用。用胆固醇生物合成途径的抑制剂mevastatin或mevinolin处理多能小鼠MSCs M2-10B4可以抑制这些细胞向功能性成骨细胞的成熟。这是通过抑制碱性磷酸酶（ALP）的活性和表达来确定的，碱性磷酸酶是成骨细胞培养分化和矿化的关键酶，以及矿化的抑制。美伐他汀治疗不影响成骨细胞特异性基因骨钙素（OCN）的表达。此外，MSCs中启动子报告子的研究表明，美伐他汀抑制ALP基因启动子的活性，提示通过胆固醇生物合成途径的衍生物进行调控。甲羟戊酸可逆转美伐他汀和美维olin的作用，而香叶香醇或法尼醇（胆固醇生物合成途径中的中间体）则不能。总之，这些结果表明，胆固醇生物合成途径的产物对于MSCs正常发育为能够形成矿化基质的功能性成骨细胞是重要的。这些分子的鉴定可能为预防骨质疏松和衰老中成骨细胞活性的下降提供新的治疗方法。
Cholesterol is an important molecule that plays a key role in regulating cellular differentiation and function. Although the possible role of lipids has been implicated in regulating osteoblastic cells, the role of cholesterol in that process is not well defined. In this study we have examined the role of the cellular cholesterol biosynthetic pathway on osteoblastic differentiation of marrow stromal cells (MSCs). Treatment of pluripotent mouse MSCs M2-10B4 with inhibitors of the cholesterol biosynthetic pathway mevastatin or mevinolin inhibited the maturation of these cells into functional osteoblastic cells. This was determined by the inhibition of the activity and expression of alkaline phosphatase (ALP), a key enzyme involved in differentiation and mineralization of osteoblastic cell cultures, as well as inhibition of mineralization. Mevastatin treatment did not affect expression of the osteoblast-specific gene osteocalcin (OCN). Furthermore, promoter-reporter studies in MSCs showed that mevastatin inhibited activity of the ALP gene promoter, suggesting regulation by derivatives of the cholesterol biosynthetic pathway. The effects of mevastatin and mevinolin were reversed by mevalonate but not by geranylgeraniol or farnesol, intermediates in the cholesterol biosynthetic pathway. Altogether, these results suggest that products of the cholesterol biosynthetic pathway are important for proper development of MSCs into functional osteoblastic cells capable of forming a mineralized matrix. Identification of those molecules may provide new therapeutic approaches to prevent the decline in osteoblastic activity in osteoporosis and aging.