Endocrine Unit, Massachusetts General Hospital and Harvard University School of Medicine, Boston, MA 02115, USA.
Biol Chem. 2011 Oct;392(10):877-85. doi: 10.1515/BC.2011.080. Epub 2011 Jul 30.
The ADAMs (a disintegrin and metalloprotease) contribute to various biological functions including the development of tissues by taking part in cell-cell and cell-matrix interactions. We previously found that ADAM15 is prominently expressed in osteoblasts and to a lesser extent in osteoclasts. The aim of this study was to investigate a possible function of ADAM15 in bone. Adult ADAM15(-/-) mice displayed an increase in bone volume and thickness with an increase in the number and activity of osteoblasts, whereas osteoclasts were apparently unaffected. We found an increase in proliferation, alkaline phosphatase (ALP) staining and nodule deposition, and mineralization in cultures of ADAM15(-/-) osteoblasts compared to wild-type osteoblasts. We also observed an increase in β-catenin immunoreactivity in the nucleus of ADAM15(-/-) osteoblasts compared to wild-type, whereas β-catenin in the membrane/cytoplasm compartment appeared to undergo increased degradation. Furthermore, cyclin D1 and c-Jun, known downstream targets of β-catenin and effectors of cell activation, were found up-regulated in absence of ADAM15. This study indicates that ADAM15 is required for normal skeletal homeostasis and that its absence causes increased nuclear translocation of β-catenin in osteoblasts leading to increased osteoblast proliferation and function, which results in higher trabecular and cortical bone mass.
ADAMs（解整合素和金属蛋白酶）通过参与细胞-细胞和细胞-基质相互作用，有助于多种生物学功能，包括组织发育。我们之前发现 ADAM15 在成骨细胞中表达明显，在破骨细胞中表达较少。本研究旨在探讨 ADAM15 在骨骼中的可能功能。成年 ADAM15(-/-) 小鼠的骨体积和厚度增加，破骨细胞数量和活性增加，而破骨细胞显然不受影响。与野生型成骨细胞相比，ADAM15(-/-)成骨细胞的培养物中增殖、碱性磷酸酶 (ALP) 染色和结节沉积以及矿化增加。与野生型相比，我们还观察到 ADAM15(-/-)成骨细胞细胞核中 β-连环蛋白免疫反应性增加，而细胞膜/细胞质部分的 β-连环蛋白似乎经历了增加的降解。此外，已知是 β-连环蛋白的下游靶标和细胞激活效应物的细胞周期蛋白 D1 和 c-Jun 在缺乏 ADAM15 时上调。这项研究表明，ADAM15 是骨骼内稳态正常所必需的，其缺失导致成骨细胞中 β-连环蛋白的核易位增加，从而导致成骨细胞增殖和功能增加，导致小梁骨和皮质骨量增加。
