title: Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice.
abstract: Tissue inhibitor of metalloproteinases-3 (TIMP-3) maintains a healthy extracellular matrix by regulating matrix metalloproteinases (MMP), disintegrin-metalloproteinases (ADAM), and disintegrin-metalloproteinases with ThromboSpondin-like motifs (ADAMTS) activity. Currently, there is a need for a comprehensive understanding of the effects of TIMP-3 on the bone quality and integrity. In this study, we examined the mechanical, morphological, and compositional properties of TIMP-3 knock out (Timp-3-/-) mouse bone. We hypothesize that the lack of TIMP-3 plays an important role in maintaining the overall bone integrity. Mechanical properties of humeri, lumbar vertebrae, and femurs from Timp-3-/-mice were determined using 3-point bending, compression, and notched 3-point bending, respectively. Morphological properties of the humeral cortical and trabecular bone and the caudal vertebrae cortical bone were evaluated using micro-computed tomography, while the composition of the femoral cortical and trabecular bone was examined using Fourier transform infrared spectroscopic imaging. Our results revealed that the integrity of the Timp-3-/-bone is compromised due to changes in its composition, structure, and mechanics. Reductions in the yield and ultimate load and stress capacity, and loss in bone fracture toughness were attributed to reduced density and thickness, and increased porosity of cortical bone. Thin trabeculae were dense, highly connected, and closely packed in Timp-3-/-bone. Furthermore, altered cortical and trabecular bone mineralization and increased compositional heterogeneity were found in Timp-3-/-bone, all being indicative of high bone remodeling. In conclusion, this study suggests that the lack of TIMP-3 is detrimental to bone development and maintenance.
authors.affiliation: Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA.
authors.forename: Brendyn
authors.initials: B
authors.lastname: Miller
authors.affiliation: Hospital for Special Surgery, New York, NY, USA.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Spevak
authors.affiliation: Hospital for Special Surgery, New York, NY, USA.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Lukashova
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
authors.forename: Behzad
authors.initials: B
authors.lastname: Javaheri
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pitsillides
authors.affiliation: Hospital for Special Surgery, New York, NY, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.affiliation: Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.affiliation: Department of Biomedical Engineering, Florida Institute of Technology, Melbourne, FL, USA. acarriero@fit.edu.
authors.forename: Alessandra
authors.identifier: 0000-0001-8103-4795
authors.initials: A
authors.lastname: Carriero
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D005260:Female; D050723:Fractures, Bone / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: Bone composition; Bone fracture; Bone strength; Bone structure; Bone tissue mineral density; Tissue inhibitor of metalloproteinase-3