Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice

Abstract

The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)‐13, produced by hypertrophic chondrocytes, and the gelatinase MMP‐9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP‐10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP‐3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP‐10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP‐10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture‐healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP‐positive cell accumulation. This phenotype can be rescued by a non‐competitive transplant of wild‐type bone marrow, indicating that MMP‐10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP‐9 processing in macrophages. Our data provide evidence of the in vivo function of MMP‐10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Matrix Metalloproteinase-10 in Kidney Injury Repair and Disease

“…In experimental animal models, expression of exogenous MMP-10 protects renal tubular epithelial cells from AKI, characterized by inhibiting tubular cells apoptosis, promoting their proliferation and regeneration [12]. These findings appear to be compatible with the notion that MMP-10 promotes tissue repair and regeneration in other organs such as liver, bone, and colon [4,9,70,71]. Consistent with that, ectopic expression of MMP-10 preserves renal function, and knockdown of endogenous MMP-10 deteriorates AKI after IRI [12].…”

The role of hypertrophic chondrocytes in regulation of the cartilage-to-bone transition in fracture healing

“…In contrast, Mmp9 -deficient mice upregulate MMP13 expression in terminal hypertrophic chondrocytes, but this upregulation will not sufficiently rescue the growth plate phenotype ( Kojima et al, 2013 ). In addition, Mmp10 -deficiency causes a similar phenotype in Mmp9 knockouts ( Valdés-Fernández et al, 2021 ), suggesting that MMP10 participates in vascularization of the growth plate, possibly in callus. Taken together, these findings indicate that MMPs play synergic, but non-compensable, roles in coupling cartilage degradation and vascularization during the cartilage-to-bone transition in fracture healing.…”