Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth
Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth
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DOI：
10.1093/hmg/ddm060
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发表时间：
2007-05-01
影响因子：
3.5
通讯作者：
Martignetti, John A.
中科院分区：
文献类型：
--
作者：
Mosig, Rebecca A.;Dowling, Oonagh;Martignetti, John A.
“消失骨”或遗传性骨质溶解/关节炎综合征代表了一组异质性骨骼疾病，其特征在于受影响骨骼和关节的矿化缺陷。不同的解剖分布，严重程度和相关的综合征的特点，基因识别在每一个'消失骨'的疾病应该提供独特的见解遗传/分子途径有助于骨骼生长和发育的整体控制。我们先前描述并证明了新的常染色体隐性骨溶解/关节炎综合征，多中心骨溶解伴关节炎（MOA）（MIM #605156），是由MMP 2基因中的失活突变引起的[Al Aqeel，A.，Al Sewairi，W.，Edress，B.，Gorlin，R.J.，Desnick，R.J.和Martignetti，J.A.（2000）遗传性多中心骨质溶解伴关节炎：一个沙特家族中类似Torg综合征的变体。Am.医学遗传学杂志，93，11-18.]。这些体内结果是违反直觉的和出乎意料的，因为先前的体外研究表明，MMP-2过表达和活性增加，而不是缺乏，将导致MOA的骨和关节特征。明显缺乏鼠模型[Itoh，T.，Ikeda，T.，Gomi，H.，Nakao，S.，铃木，T.和Itohara，S.（1997）明胶酶A（基质金属蛋白酶2）缺陷小鼠中β-淀粉样前体蛋白的分泌不变。生物化学杂志，272、22389-22392。]阻碍了对疾病发病机制的研究，更根本的是，阻碍了对单一蛋白水解酶功能丧失如何导致骨丢失明显增加的矛盾的研究。在这里，我们报告说，Mmp 2-/-小鼠显示人类MOA的衰减功能，包括骨密度的进行性损失，关节软骨破坏和异常长骨和颅面发育。此外，这些变化与体内成骨细胞和破骨细胞数量的显着和发育限制性减少有关。Mmp 2-/-小鼠在4天的生命中具有比对照同窝小鼠少50%的成骨细胞和破骨细胞，但这些差异在4周龄时几乎消失。此外，尽管在8周龄时体内细胞数量正常，但Mmp 2-/-骨髓细胞不能有效地支持培养物中的成骨细胞和破骨细胞生长和分化。在人SaOS 2和鼠MC 3 T3成骨细胞系中使用siRNA靶向抑制MMP-2导致细胞增殖率降低。综上所述，我们的研究结果表明，MMP-2在早期骨骼发育和骨细胞生长和增殖中起着直接作用。因此，Mmp 2-/-小鼠为研究人类疾病的病理生理机制和确定MMP-2的体内生理作用提供了有价值的生物资源。
The 'vanishing bone' or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity and associated syndromic features, gene identification in each 'vanishing bone' disorder should provide unique insights into genetic/molecular pathways contributing to the overall control of skeletal growth and development. We previously described and then demonstrated that the novel autosomal recessive osteolysis/arthritis syndrome, multicentric osteolysis with arthritis (MOA) (MIM #605156), was caused by inactivating mutations in the MMP2 gene [Al Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R.J., Desnick, R.J. and Martignetti, J.A. (2000) Inherited multicentric osteolysis with arthritis: A variant resembling Torg syndrome in a Saudi family. Am. J. Med. Genet., 93, 11-18.]. These in vivo results were counterintuitive and unexpected since previous in vitro studies suggested that MMP-2 overexpression and increased activity, not deficiency, would result in the bone and joint features of MOA. The apparent lack of a murine model [Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T. and Itohara, S. (1997) Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol Chem., 272, 22389-22392.] has hindered studies on disease pathogenesis and, more fundamentally, in addressing the paradox of how functional loss of a single proteolytic enzyme results in an apparent increase in bone loss. Here, we report that Mmp2-/- mice display attenuated features of human MOA including progressive loss of bone mineral density, articular cartilage destruction and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2-/- mice have similar to 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life but these differences have nearly resolved by 4 weeks of age. In addition, despite normal cell numbers in vivo at 8 weeks of life, Mmp2-/- bone marrow cells are unable to effectively support osteoblast and osteoclast growth and differentiation in culture. Targeted inhibition of MMP-2 using siRNA in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP-2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2-/- mice provide a valuable biological resource for studying the pathophysiological mechanisms underlying the human disease and defining the in vivo physiological role of MMP-2.