Matrix metalloproteinase–13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance

Abstract

Like bone mass, bone quality is specified in development, actively maintained post-natally, and disrupted by disease. The roles of osteoblasts, osteoclasts, and osteocytes in the regulation of bone mass are increasingly well defined. However, the cellular and molecular mechanisms by which bone quality is regulated remain unclear. Proteins that remodel bone extracellular matrix, such as the collagen-degrading matrix metalloproteinase (MMP)-13, are likely candidates that regulate bone quality. Using MMP-13 deficient mice, we examined the role of MMP-13 in the remodeling and maintenance of bone matrix and subsequent fracture resistance. Throughout the diaphysis of MMP-13-deficient tibiae, we observed elevated nonenzymatic crosslinking and concentric regions of hypermineralization, collagen disorganization, and canalicular malformation. These defects localize to the same mid-cortical bone regions where osteocyte lacunae and canaliculi exhibit MMP-13 and tartrate-resistant acid phosphatase (TRAP) expression, as well as the osteocyte marker Sclerostin. Despite otherwise normal measures of osteoclast and osteoblast function, dynamic histomorphometry revealed that remodeling of osteocyte lacunae is impaired in MMP-13−/− bone. Analysis of MMP-13−/− mice and their wild-type littermates in normal and lactating conditions showed that MMP-13 is not only required for lactation-induced osteocyte perilacunar remodeling, but also for the maintenance of bone quality. The loss of MMP-13, and the resulting defects in perilacunar remodeling and matrix organization, compromise MMP-13−/− bone fracture toughness and post-yield behavior. Taken together, these findings demonstrate that osteocyte perilacunar remodeling of mid-cortical bone matrix requires MMP-13 and is essential for the maintenance of bone quality.

Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

“…Indeed, consistent with the pro-osteoclastogenic effects of exogenous MMP-13 found in vitro, Mmp13 -/-OCLs also showed defects in form and function in vitro. Underlining these effects, Mmp13 -/-mice have previously been reported to show an osteopetrotic phenotype with increased trabecular bone volume and bone mineral density (16,56,57), along with increased callus bone volume and bone mineral density during active bone remodeling following fracture (10). Given these findings, we considered the possibility that MMP-13 might also affect osteoblast (OB) formation or MM cell behavior itself, as both cell types express the metalloproteinase (Supplemental Figure 17A).…”

“…MMP-13 is a member of a family of zinc-and calcium-dependent proteolytic enzymes that degrade extracellular matrix components during normal physiological processes (e.g., embryonic development, reproduction, tissue remodeling, and angiogenesis) as well as in pathological conditions such as osteoarthritis, tumor invasion, and metastasis (8,9). In each of these scenarios, the key functional activities of MMP-13 have been linked directly to its ability to degrade interstitial collagen, a critical structural component of all connective tissues, including bone, as well as other matrix-associated targets (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). However, in contrast to studies highlighting the degradative activities of the metalloproteinase, we now report that MM-derived MMP-13 serves as a potent secretagogue of OCL fusion and bone-resorptive activity independently of its proteolytic activity by triggering the ERK1/2-dependent regulation of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and dendrocyte-expressed 7 transmembrane (DC-STAMP) expression.…”

Polarization in Raman spectroscopy helps explain bone brittleness in genetic mouse models

“…17 This is perhaps not too surprising, given a growing body of evidence that polarized Raman intensity varies with collagen direction 10,18 and can even be used to determine collagen orientation in bone. 19 Other genetic mouse models have also demonstrated brittle bone phenotypes that are not necessarily explained by composition but are related to matrix organization, 20,21 and hence may benefit from polarization RS. We recently reported that there are polarizationrelated changes in the RS peak ratios of bones lacking the activating transcription factor 4 (ATF4), implying an organizational component to the phenotype that includes toughness loss and decreased fracture toughness, 22 but it is unclear to what extent these polarization RS changes are predictive of mechanical bone quality.…”

Matrix metalloproteinases in bone development and pathology: current knowledge and potential clinical utility

“…This subsequently results in impairment of bone matrix organization and cartilage ECM remodeling in these animals, which leads to a reduction in both toughness and fracture resistance of their long bones, but ultimately the mice show no notable abnormalities in their long bone development. [51][52][53] MMP-13 is a downstream target of the transcription factor Cbfa1/Runx2 in hypertrophic chondrocytes, as Cbfa1 knockout mice fail to express MMP-13 during fetal development.…”