Abstract
Tissue inhibitor of metalloproteinases-3 (TIMP-3) regulates extracellular matrix via its inhibition of matrix metalloproteinases and membrane-bound sheddases. Timp-3 is expressed at multiple sites of extensive tissue remodelling. This extends to bone where its role, however, remains largely unresolved. In this study, we have used Micro-CT to assess bone mass and architecture, histological and histochemical evaluation to characterise the skeletal phenotype of Timp-3 KO mice and have complemented this by also examining similar indices in mice harbouring a Timp-3 transgene driven via a Col-2a-driven promoter to specifically target overexpression to chondrocytes. Our data show that Timp-3 deficiency compromises tibial bone mass and structure in both cortical and trabecular compartments, with corresponding increases in osteoclasts. Transgenic overexpression also generates defects in tibial structure predominantly in the cortical bone along the entire shaft without significant increases in osteoclasts. These alterations in cortical mass significantly compromise predicted tibial load-bearing resistance to torsion in both genotypes. Neither Timp-3 KO nor transgenic mouse growth plates are significantly affected. The impact of Timp-3 deficiency and of transgenic overexpression extends to produce modification in craniofacial bones of both endochondral and intramembranous origins. These data indicate that the levels of Timp-3 are crucial in the attainment of functionally-appropriate bone mass and architecture and that this arises from chondrogenic and osteogenic lineages.
Highlights
Bone comprises a predominantly type I collagen-rich, mineralised extracellular matrix (ECM) that is synthesised by osteoblasts, degraded by osteoclasts and populated by osteocytes
We found that both Timp-3 deficiency and transgenic expression resulted in lower bone mineral density (BMD) in both trabecular and cortical compartments compared with their respective WTs; these changes only reached levels of statistical significance in KO mice compared with WTB6 control (p 0.01, Table 1)
Based on previous studies using matrix metalloproteinases (MMPs) knockout mice, we predicted that Timp-3 deficiency would compromise bone mass and structure, and perhaps bone mineral density
Summary
Bone comprises a predominantly type I collagen-rich, mineralised extracellular matrix (ECM) that is synthesised by osteoblasts, degraded by osteoclasts and populated by osteocytes. All bones of the appendicular skeleton form via endochondral ossification, involving calcification of a collagen type II-rich ECM followed by its replacement with bone. Some bones of the cranial skeleton can form via intramembranous ossification, the direct differentiation of mesenchymal cells into osteoblasts [1]. The fate of mesenchymal cells and directions of this skeletal differentiation are governed mainly by different signalling pathways [2]. Many factors including the Metzincin family, of which the matrix metalloproteinases (MMPs) sub-family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs participate in this ECM regulation [3]. Other enzymes such as “a disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) [4] and ADAM, often called “sheddases”, affect cellular behaviour by proteolytically releasing extracellular domains of cell surface molecules such as membranebound growth factors, cytokines and their receptors [5]
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