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缺乏组织蛋白酶K的小鼠尽管骨量高,但仍维持骨重塑并出现骨脆性。

Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass.

作者信息

Li Chao Yang, Jepsen Karl J, Majeska Robert J, Zhang Jian, Ni Rujing, Gelb Bruce D, Schaffler Mitchell B

机构信息

Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, New York 10029-6574, USA

出版信息

J Bone Miner Res. 2006 Jun;21(6):865-75. doi: 10.1359/jbmr.060313.

Abstract

UNLABELLED

Bone microstructural and biomechanical properties were analyzed in mice genetically lacking cathepsin K (CatK). CatK deficiency (CatK(-/-)) produced mild osteopetrosis, elevated numbers of osteoclasts, regions of disorganized bone microstructure, and increased bone fragility, showing how chronic alteration of enzyme activity during skeletal development dramatically affects bone organization and function.

INTRODUCTION

Mouse models of CatK deficiency recapitulate the osteopetrosis of human pyknodysostosis and allow study of clinically relevant issues: how inhibition of this enzyme activity affects bone integrity structurally and biomechanically. To address these questions, we generated CatK-deficient mice by targeted disruption of the Ctsk gene and compared their bone structural and mechanical properties with wildtype (WT) controls.

MATERIALS AND METHODS

Standard histomorphometric and biomechanical analyses were performed on femora from C57BL/6J male and female CatK(-/-), CatK(+/-), and WT mice.

RESULTS

CatK(-/-) femora exhibited the mild metaphyseal osteopetrosis, a greater cortical bone area and thickness, normal bone strength, but a high degree of brittleness (nearly 50-70% decrease in postyield displacement versus WT) and a 30-40% reduction in the work-to-failure. In cancellous bone, osteoclast numbers and resorption surface were increased markedly (approximately 150% and 50%, respectively), despite the overall decrease in net bone resorption for CatK-deficient mice. Bone formation indices were altered in CatK(-/-) mice as well, with significant increases in mineral appositional rate, but not in bone formation surface; these data suggest difference in osteoblast work but not in their recruitment in CatK deficiency. CatK-deficient cortical bones had large areas of woven bone and intracortical resorption spaces within the disorganized tissue. Bone phenotype in CatK(-/-) was similar in males and females.

CONCLUSIONS

Genetic CatK deficiency in mice results not only in the impairment of osteoclast function and osteopetrosis, but also altered osteoblast function, defective tissue organization, and very brittle bones. Whether this bone fragility in CatK deficiency results entirely from indirect effects of suppressed bone turnover because of impaired osteoclast function or perhaps represents a previously unappreciated more direct role for CatK in bone formation remains to be established.

摘要

未标记

对基因敲除组织蛋白酶K(CatK)的小鼠的骨微观结构和生物力学特性进行了分析。CatK缺乏(CatK(-/-))导致轻度骨质石化、破骨细胞数量增加、骨微观结构紊乱区域以及骨脆性增加,这表明骨骼发育过程中酶活性的慢性改变如何显著影响骨组织和功能。

引言

CatK缺乏的小鼠模型重现了人类致密性成骨不全症的骨质石化,并允许研究临床相关问题:这种酶活性的抑制如何在结构和生物力学上影响骨完整性。为了解决这些问题,我们通过靶向破坏Ctsk基因生成了CatK缺陷小鼠,并将它们的骨结构和力学特性与野生型(WT)对照进行比较。

材料与方法

对C57BL/6J雄性和雌性CatK(-/-)、CatK(+/-)和WT小鼠的股骨进行标准组织形态计量学和生物力学分析。

结果

CatK(-/-)股骨表现出轻度干骺端骨质石化、更大的皮质骨面积和厚度、正常的骨强度,但脆性程度很高(屈服后位移比WT降低近50-70%),破坏功降低30-40%。在松质骨中,尽管CatK缺陷小鼠的净骨吸收总体减少,但破骨细胞数量和吸收表面显著增加(分别约为150%和50%)。CatK(-/-)小鼠的骨形成指标也发生了改变,矿化沉积率显著增加,但骨形成表面没有增加;这些数据表明CatK缺乏时成骨细胞的工作方式存在差异,但成骨细胞的募集没有差异。CatK缺陷的皮质骨在紊乱组织内有大面积的编织骨和皮质内吸收空间。CatK(-/-)的骨表型在雄性和雌性中相似。

结论

小鼠基因敲除CatK不仅导致破骨细胞功能受损和骨质石化,还改变了成骨细胞功能、组织结构缺陷以及骨骼非常脆弱。CatK缺乏时这种骨脆性是否完全由破骨细胞功能受损导致的骨转换抑制的间接影响引起,或者是否可能代表CatK在骨形成中以前未被认识到的更直接作用,仍有待确定。

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