Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-null mice, as well as cathepsin K-mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K-independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone- or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.

中文翻译：

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破骨细胞介导的骨吸收受分泌的和膜连接的金属蛋白酶的补偿网络控制。

破骨细胞在正常生长和发育期间以及从骨质疏松症到骨转移的病理状态中都积极地重塑骨骼的矿物质和蛋白质成分。半胱氨酸蛋白酶组织蛋白酶K赋予破骨细胞以强效的I型胶原分解活性。但是，组织蛋白酶K无效的小鼠以及组织蛋白酶K突变的人类，仍通过尚未确定的效应子继续重塑骨骼并降解胶原蛋白。在这里，我们确定破骨细胞中由组织蛋白酶K独立的胶原蛋白分解系统，该系统由分泌型基质金属蛋白酶MMP9和膜锚定基质金属蛋白酶MMP14的功能冗余网络组成。出乎意料的是，虽然分别删除两种蛋白酶中的任何一种都会使骨吸收保持完整，Mmp9和Mmp14的双重靶向抑制了体外和体内小鼠破骨细胞和体外人破骨细胞的吸收活性。在体内，Mmp9 / Mmp14条件性双敲除小鼠的骨密度显着增加，并且对甲状旁腺激素或卵巢切除术引起的病理性骨丢失显示出高度保护的状态。总之，这些研究表征了可在小鼠和人类破骨细胞中起作用的胶原蛋白水解系统，并确定MMP9 / MMP14轴是用于治疗骨萎缩性疾病状态的潜在靶标。