title: Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo.
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.
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Behzad
authors: http://orcid.org/0000-0001-7941-3104
authors: B
authors: Javaheri
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Mark
authors: M
authors: Hopkinson
authors: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors: Blandine
authors: B
authors: Poulet
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Andrea S
authors: AS
authors: Pollard
authors: Department of Mechanical and Industrial Engineering, Northeastern University, Boston, Massachusetts, United States of America.
authors: Sandra J
authors: SJ
authors: Shefelbine
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Yu-Mei
authors: YM
authors: Chang
authors: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, United Kingdom.
authors: Philippa
authors: P
authors: Francis-West
authors: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors: George
authors: G
authors: Bou-Gharios
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Andrew A
authors: AA
authors: Pitsillides
mesh_terms: D000818:Animals; D015519:Bone Density; D000071556:Cancellous Bone / Q000378:metabolism / Q000473:pathology*; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases