Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity

Poulet, Blandine; Liu, Ke; Plumb, Darren; Vo, Phoung; Shah, Mittal; Staines, Katherine; Sampson, Alexandra; Nakamura, Hiroyuki; Nagase, Hideaki; Carriero, Alessandra; Shefelbine, Sandra; Pitsillides, Andrew A.; Bou-Gharios, George

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.

Citation

Poulet, B., Liu, K., Plumb, D., Vo, P., Shah, M., Staines, K., Sampson, A., Nakamura, H., Nagase, H., Carriero, A., Shefelbine, S., Pitsillides, A. A., & Bou-Gharios, G. (2016). Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity. PLOS ONE, 11(12), Article e0167971. https://doi.org/10.1371/journal.pone.0167971

• Journal Article Type: Article
• Acceptance Date: Nov 23, 2016
• Online Publication Date: Dec 21, 2016
• Publication Date: Dec 21, 2016
• Deposit Date: Jan 13, 2017
• Publicly Available Date: Jul 30, 2019
• Journal: PLOS ONE
• Print ISSN: 1932-6203
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 12
• Article Number: e0167971
• DOI: https://doi.org/10.1371/journal.pone.0167971
• Keywords: Biochemistry, Genetics and Molecular Biology(all); Agricultural and Biological Sciences(all); Medicine(all)
• Public URL: http://researchrepository.napier.ac.uk/Output/462382
• Contract Date: Jan 13, 2017