Jilka R L, Weinstein R S, Takahashi K, Parfitt A M, Manolagas S C
Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
J Clin Invest. 1996 Apr 1;97(7):1732-40. doi: 10.1172/JCI118600.
Bone marrow is the principal site for osteoclastogenesis and osteoblastogenesis; and an increase in the former has been linked with bone loss caused by acute loss of gonadal steroids. We have now used an established murine model of accelerated senescence and osteopenia (SAMP6) to test the hypothesis that reduced osteoblastogenesis is linked with decreased bone mass. At 1 mo of age, the number of osteoblast progenitors in SAMP6 marrow was indistinguishable from controls; however a threefold decrease was found at 3-4 mo of age. Impaired osteoblast formation was temporally associated with decreased bone formation and decreased bone mineral density, as determined by histomorphometric analysis of tetracycline-labeled cancellous bone and dual-energy x-ray absorptiometry, respectively. Osteoclastogenesis determined in ex vivo bone marrow cultures was also decreased in these mice, as was the number of osteoclasts in histologic sections. Moreover, unlike controls, senescence-accelerated mice failed to increase osteoclast development after gonadectomy. The osteoclastogenesis defeat was secondary to impaired osteoblast formation as evidenced by the fact that osteoclastogenesis could be restored by addition of osteoblastic cells from normal mice. These findings provide the first demonstration of a link between low bone mineral density and decreased osteoblastogenesis in the bone marrow and validate the senescence-accelerated mouse as a model of involutional osteopenia.
骨髓是破骨细胞生成和成骨细胞生成的主要部位；前者的增加与性腺类固醇急性缺失导致的骨质流失有关。我们现在使用已建立的加速衰老和骨质减少的小鼠模型（SAMP6）来检验以下假设：成骨细胞生成减少与骨量减少有关。在1月龄时，SAMP6骨髓中成骨细胞祖细胞的数量与对照组无差异；然而，在3 - 4月龄时发现减少了三倍。通过对四环素标记的松质骨进行组织形态计量分析和双能X线吸收法分别测定，成骨细胞形成受损在时间上与骨形成减少和骨矿物质密度降低相关。在这些小鼠的离体骨髓培养物中测定的破骨细胞生成也减少，组织学切片中的破骨细胞数量也减少。此外，与对照组不同，衰老加速小鼠在去势后未能增加破骨细胞的发育。破骨细胞生成失败继发于成骨细胞形成受损，这一事实表明通过添加正常小鼠的成骨细胞可以恢复破骨细胞生成。这些发现首次证明了低骨矿物质密度与骨髓中成骨细胞生成减少之间的联系，并验证了衰老加速小鼠作为 involutional 骨质减少模型的有效性。
