Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases
发布时间：2024-10-26
点击次数：
- DOI码：
- 10.1126/scitranslmed.aaw6143
- 发表刊物：
- Sci Transl Med
- 摘要：
- 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.
- 合写作者：
- Tang Y, Li XY, Keller ET, Yang J, Cho JS, Feinberg TY
- 第一作者：
- Zhu L
- 通讯作者：
- Weiss SJ
- 卷号：
- 12
- 期号：
- 529
- 页面范围：
- eaaw6143
- 是否译文：
- 否
- 发表时间：
- 2020-02-25
- 收录刊物：
- SCI