Research ArticleBone

Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases

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Science Translational Medicine  05 Feb 2020:
Vol. 12, Issue 529, eaaw6143
DOI: 10.1126/scitranslmed.aaw6143

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Codependent deconstruction

Bone homeostasis encompasses a balancing act between formation of new bone and remodeling and resorption of existing bone. For patients with bone-wasting disorders such as osteoporosis, bone resorption predominates. To identify potential therapeutic targets in maladaptive bone resorption, Zhu et al. investigated mechanisms of collagenolytic activity in osteoclasts. They found that dual deletion of the matrix metalloproteinases MMP9 and MMP14 inhibited murine and human osteoclast activity, increased bone density, and prevented against pathogenic bone loss in mice. Dual targeting of MMP9 and MMP14 could potentially help treat bone-wasting diseases.

Abstract

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.

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