Session Title: Biology and Pathology of Bone and Joint: Osteoarthritis
Session Type: Abstract Submissions (ACR)
Background/Purpose: To assess the disease modifying (DMOA) effect of strontium ranelate (SrRan) under therapeutic conditions on the progression of structural changes and on the major pathways involved in these changes in an experimental osteoarthritis (OA) dog model.
Methods: Dogs were divided into 4 therapeutic groups and underwent sectioning of the anterior cruciate ligament of the right knee and, 4 weeks after surgery, received oral treatment with SrRan 25, 50 or 75 mg/kg, or placebo for 12 weeks. Severity of cartilage lesions was scored macroscopically, and specimens of cartilage, subchondral bone and synovium were processed for histology, including picrosirius red staining and quantitative PCR (RT-PCR). Specific probes were used to quantify the messenger RNA of MMP-1, MMP-13, ADAMTS5, cathepsin K and interleukin-1β (IL-1β). Histomorphometry of the subchondral bone and a pharmacokinetic analysis of strontium (Sr) blood levels were also performed. The level of CTX-II in serum was quantified by ELISA.
Results: At steady state, Sr blood exposures were found to be within the clinical therapeutic range of OA patients treated with 1 or 2 g/day of SrRan, and Sr concentrations in synovial fluid correlated with Sr blood concentrations. SrRan treatment significantly reduced the progression of OA cartilage lesions at all dosages tested (p<0.05). Picrosirius staining also showed a significantly better preservation of the collagen network in dogs treated with SrRan at 50 and 75 mg/kg/day (p<0.03). The thickening of the subchondral plate found in the OA placebo treated dogs was reduced by SrRan treatment (50 mg/kg/day, p<0.02). The increased gene expression levels of MMP-1, MMP-13, ADAMTS5 and cathepsin K found in OA cartilage were all reduced by SrRan treatment (75 mg/kg/day, p=0.02, p=0.03, p=0.06, p<0.0001, respectively). A significant suppression of the increased levels of IL-1β in OA synovium by SrRan was also found (50 and 75 mg/kg/day, p=0.05). The serum level of CTX-II was significantly reduced at sacrifice in dogs treated with 50 and 75 mg/kg SrRan.
Conclusion: This study is the first to demonstrate that SrRan globally reduced the progression of OA structural changes, both cartilage lesions and subchondral bone sclerosis, in an in vivo animal model. The inhibition of the synthesis of several key pathophysiological pathways may have contributed to the protective effect of SrRan.
J. P. Pelletier,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disease-modifying-effect-of-strontium-ranelate-in-experimental-dog-osteoarthritis-inhibition-of-major-catabolic-pathways/