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SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2018 Jun; Vol. 33 (6), pp. 1105-1113. Date of Electronic Publication: 2018 Apr 02. - Publication Year :
- 2018
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Abstract
- 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 (SOST <superscript>TG</superscript> ) and knockout (Sost <superscript>-/-</superscript> ) mice. Here we report that SOST <superscript>TG</superscript> mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post-injury compared with wild-type (WT) controls and Sost <superscript>-/-</superscript> . In addition, SOST <superscript>TG</superscript> built ∼50% and ∼65% less osteophyte volume than WT and Sost <superscript>-/-</superscript> , respectively. Quantification of metalloproteinase (MMP) activity showed that SOST <superscript>TG</superscript> had ∼2-fold less MMP activation than WT or Sost <superscript>-/-</superscript> , 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 TNFα and NF-κB 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.<br /> (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Binding Sites
Extracellular Matrix drug effects
Extracellular Matrix metabolism
Genetic Markers
Humans
Intercellular Signaling Peptides and Proteins
Mice, Inbred C57BL
Models, Biological
NF-kappa B metabolism
Osteophyte metabolism
Phenotype
Recombinant Proteins pharmacology
Tumor Necrosis Factor-alpha metabolism
Up-Regulation drug effects
Anterior Cruciate Ligament Injuries metabolism
Anterior Cruciate Ligament Injuries pathology
Bone Morphogenetic Proteins metabolism
Glycoproteins metabolism
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase 3 metabolism
Osteoarthritis, Knee enzymology
Osteoarthritis, Knee pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1523-4681
- Volume :
- 33
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 29377313
- Full Text :
- https://doi.org/10.1002/jbmr.3397