A Crucial Role for Matrix Metalloproteinase 2 in Osteocytic Canalicular Formation and Bone Metabolism

Abstract

Bone is continuously remodeled to adopt a volume appropriate for the local environment; the amount of bone deposited depends on the balance between bone formation and resorption by bone cells, osteoblasts, osteoclasts, and osteocytes (1). Osteoblasts are bone-forming cells that differentiate from mesenchymal stem cells and secrete extracellular matrix (ECM) 4 proteins, which are subsequently mineralized. Osteoclasts are bone-resorbing cells that differentiate from hematopoietic stem cells and degrade bone ECM proteins after demineralization in the extracellular space (Howship's lacunae) adjacent to the ruffled borders. In contrast to osteoblasts and osteoclasts, which act at bone surfaces, osteocytes, cells of osteoblastic lineage, are embedded in bone and are terminally differentiated. Osteocytes extend their dendritic processes into the bone matrix to constitute a well developed canalicular network with other cells. Although osteocytes are the most abundant cell type in bone tissue, their role in bone metabolism is not firmly established.ECM production and degradation by bone cells are critical steps in bone metabolism (1), and disturbed ECM turnover leads to bone disease. Type I collagen is a major ECM component. Secreted type I collagen molecules are processed by propeptidases and cross-linked by lysyl oxidases into mature collagen. Mutations of genes encoding type I collagen cause the bone disease osteogenesis imperfecta (2). Type I collagens are mainly degraded by matrix metalloproteinases (MMPs), which exert their enzymatic activity at a neutral pH in a zinc ion-dependent manner (3, 4). Several MMPs are expressed in bone tissue (5-9). MMPs may play a role in osteoclastic bone resorption (4, 5). Osteoblasts and osteocytes also produce MMPs such as MMP-2 and MMP-13 (7-9). Recent linkage analysis suggests that a loss of function mutation of MMP2 causes a human autosomal recessive disorder with multicentric nodulosis, arthropathy with joint erosion, and osteolysis, termed NAO syndrome (10, 11). This syndrome also includes facial abnormalities and generalized * This work was supported in part by a grant from the Ministry for Welfare and Health of Japan (to S. I.), by a Sasagawa Scientific Research Grant from the Japan Science Society (to K. I.), by a grant from the Japan Space Forum, National Space Development Agency of Japan (NASDA) (to N. M.), and by a research grant from the National Institutes of Health (to S. M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 4 The abbreviations used are: ECM, extracellular matrix; DMP-1, dentin matrix protein 1; DMEM, Dulbecco's modified Eagle's medium; MMP, matrix metalloproteinase; NAO, nodulosis, arthropathy, and osteolysis; BMD, bone mineral density; pQCT, peripheral quantitative computed tomography; MAR, mineral apposition rate; BFR/BS, ratio of bone formation rate to bone surface.

Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone

“…The lack of a difference in the size of diaphysis (I min ) and trabecular bone volume in the tibia metaphysis between WT and Mmp2 À/À mice reflects the reported observations of osteoblast function by Inoue and colleagues, (11) who found, for long bones, little difference in mineralization apposition rate and bone-formation rate per bone surface between the two genotypes. They also did not detect any appreciable differences in osteoblastic nodule formation or osteoclast formation in in vitro bone marrow cell culture assays.…”

“…(6,34) MMP-2, on the other hand, is expressed primarily by osteoblasts and plays a yet to be fully understood role in canaliculi formation. (11,35) Specifically, Mmp2 À/À bones display a . Fig.…”

“…disrupted canalicular network but with little osteocyte death, (11,35) and this phenomenon may impede the accumulation of mineral within the matrix. Thus this could explain the observed decrease in mineralization at the tissue level in Mmp2…”

“…The generation of Mmp2 null mice provided insight into how this osteoblast-derived MMP affects the development of canaliculi. (11) Mmp2 À/À bones were reported to have lower bone mineral density (BMD) than WT bones with no apparent difference in the length, suggesting MMP-2 has a compositional influence on the biomechanical properties of bone. (11) Indeed, we recently observed that the degree of mineralization of the midshaft strongly correlated with estimated bending strength of the femur across WT and Mmp2…”

Matrix metalloproteinases and the regulation of tissue remodelling

“…Although the Mmp2-knockout mouse has only a subtle skeletal defect 50 , human MMP2 mutants have an osteolytic (vanishing bone) syndrome, which involves progressive destruction and resorption of bone, as well as dwarfism and arthritis 47 . The defects of this syndrome are similar to the phenotype of Mmp14-mutant mice.…”