title: Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity.
abstract: Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex process of bone formation and growth. We generated a transgenic mouse line to overexpress TIMP3 in mouse chondrocytes using the Col2a1-chondrocyte promoter. This overexpression in cartilage resulted in a transient shortening of growth plate in homozygote mice but bone length was restored at eight weeks of age. However, tibial bone structure and mechanical properties remained compromised. Despite no transgene expression in adult osteoblasts from transgenic mice in vitro, their differentiation capacity was decreased. Neonates, however, did show transgene expression in a subset of bone cells. Our data demonstrate for the first time that transgene function persists in the chondro-osseous lineage continuum and exert influence upon bone quantity and quality.
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Apex building, Liverpool, United Kingdom.
authors.forename: Blandine
authors.identifier: http://orcid.org/0000-0002-9224-5253
authors.initials: B
authors.lastname: Poulet
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Apex building, Liverpool, United Kingdom.
authors.forename: Ke
authors.identifier: http://orcid.org/0000-0003-3769-1653
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Apex building, Liverpool, United Kingdom.
authors.forename: Darren
authors.initials: D
authors.lastname: Plumb
authors.affiliation: Kennedy Institute of Rheumatology, Oxford, United Kingdom.
authors.forename: Phoung
authors.initials: P
authors.lastname: Vo
authors.affiliation: Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors.forename: Mittal
authors.initials: M
authors.lastname: Shah
authors.affiliation: Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Staines
authors.affiliation: Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sampson
authors.affiliation: Kennedy Institute of Rheumatology, Oxford, United Kingdom.
authors.forename: Hiroyuki
authors.identifier: http://orcid.org/0000-0002-2524-3063
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Kennedy Institute of Rheumatology, Oxford, United Kingdom.
authors.forename: Hideaki
authors.identifier: http://orcid.org/0000-0002-8563-2263
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, United States of America.
authors.forename: Alessandra
authors.identifier: http://orcid.org/0000-0001-8103-4795
authors.initials: A
authors.lastname: Carriero
authors.affiliation: College of Engineering, Northeastern University, Boston, MA, United States of America.
authors.forename: Sandra
authors.initials: S
authors.lastname: Shefelbine
authors.affiliation: Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pitsillides
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Apex building, Liverpool, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology / Q000502:physiology*; D002356:Cartilage / Q000378:metabolism*; D002478:Cells, Cultured; D024043:Collagen Type II / Q000235:genetics; D005269:Femur / Q000000981:diagnostic imaging / Q000502:physiology; D006132:Growth Plate / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D011401:Promoter Regions, Genetic; D013718:Tensile Strength; D013977:Tibia / Q000000981:diagnostic imaging / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D024043:Collagen Type II; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3