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Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling.

ABSTRACT: Connexin43 (Cx43) is the main gap junction protein expressed in bone forming cells, where it modulates peak bone mass acquisition and cortical modeling. Genetic ablation of the Cx43 gene (Gja1) results in cortical expansion with accentuated periosteal bone formation associated with decreased expression of the Wnt inhibitor sclerostin. To determine whether sclerostin (Sost) down-regulation might contribute to periosteal expansion in Gja1 deficient bones, we took a gene interaction approach and crossed mice harboring germline null alleles for Gja1 or Sost to generate single Gja1+/-and Sost+/-and double Gja1+/-;Sost+/-heterozygous mice. In vivo ?CT analysis of cortical bone at age 1 and 3 months confirmed increased thickness in Sost-/-mice, but revealed no cortical abnormalities in single Gja1+/-or Sost+/-mice. Double heterozygous Gja1+/-Sost+/-also showed no differences in mineral density, cortical thickness, width or geometry relative to wild type control mice. Likewise, 3-point bending measurement of bone strength revealed no significant differences between double Gja1+/-;Sost+/-or single heterozygous and wild type mice. Although these data do not exclude a contribution of reduced sclerostin in the cortical expansion seen in Gja1 deficient bones, they are not consistent with a strong genetic interaction between Sost and Gja1 dictating cortical modeling.

SUBMITTER: Grimston SK

PROVIDER: S-EPMC5693294 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling.

Grimston Susan K SK Fontana Francesca F Watkins Marcus M Civitelli Roberto R

PloS one 20171117 11

Connexin43 (Cx43) is the main gap junction protein expressed in bone forming cells, where it modulates peak bone mass acquisition and cortical modeling. Genetic ablation of the Cx43 gene (Gja1) results in cortical expansion with accentuated periosteal bone formation associated with decreased expression of the Wnt inhibitor sclerostin. To determine whether sclerostin (Sost) down-regulation might contribute to periosteal expansion in Gja1 deficient bones, we took a gene interaction approach and cr ...[more]

PMID: 29149200

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Project description:Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there are ?900,000 knee injuries in the United States, which account for ?12% of all osteoarthritis (OA) cases. PTOA leads to reduced physical activity, deconditioning of the musculoskeletal system, and in severe cases requires joint replacement to restore function. Therefore, treatments that would prevent cartilage degradation post-injury would provide attractive alternatives to surgery. Sclerostin (Sost), a Wnt antagonist and a potent negative regulator of bone formation, has recently been implicated in regulating chondrocyte function in OA. To determine whether elevated levels of Sost play a protective role in PTOA, we examined the progression of OA using a noninvasive tibial compression overload model in SOST transgenic (SOSTTG ) and knockout (Sost-/- ) mice. Here we report that SOSTTG mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post-injury compared with wild-type (WT) controls and Sost-/- . In addition, SOSTTG built ?50% and ?65% less osteophyte volume than WT and Sost-/- , respectively. Quantification of metalloproteinase (MMP) activity showed that SOSTTG had ?2-fold less MMP activation than WT or Sost-/- , and this was supported by a significant reduction in MMP2/3 protein levels, suggesting that elevated levels of SOST inhibit the activity of proteolytic enzymes known to degrade articular cartilage matrix. Furthermore, intra-articular administration of recombinant Sost protein, immediately post-injury, also significantly decreased MMP activity levels relative to PBS-treated controls, and Sost activation in response to injury was TNF? and NF-?B dependent. These results provide in vivo evidence that sclerostin functions as a protective molecule immediately after joint injury to prevent cartilage degradation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Dataset Information

Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling.

Publications

Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling.

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