Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1β in the synovium.
OBJECTIVE
To explore the disease-modifying effect, under therapeutic conditions, of strontium ranelate (SrRan) on the progression of joint structural changes and on the major pathophysiological pathways in an experimental osteoarthritis dog model.


METHODS
Dogs underwent sectioning of the anterior cruciate ligament, and 4 weeks after surgery received oral treatment of SrRan 25, 50 or 75 mg/kg per day, or placebo for 12 weeks. Methods included macroscopy, picrosirius red staining, histology, subchondral bone histomorphometry, quantitative PCR, and ELISA for CTX-II level in serum. Strontium plasma and synovial fluid levels were also measured.


RESULTS
At steady state, strontium blood exposures were within the clinical therapeutic range of osteoarthritis patients and correlated with strontium concentrations in synovial fluid. SrRan treatment significantly reduced the osteoarthritis cartilage lesions at all doses tested (p≤0.05). Significantly better preservation of the collagen network was also found in SrRan-treated dogs at 50 and 75 mg/kg per day (p=0.03). The osteoarthritis subchondral bone thickening observed in osteoarthritis-placebo dogs was significantly reduced by SrRan at 50 mg/kg per day (p=0.02). The increased gene expression levels of MMP-1, MMP-13 and cathepsin K in osteoarthritis cartilage were all significantly reduced by SrRan at 75 mg/kg per day (p≤0.03) as were, in osteoarthritis synovium, IL-1β at 50 and 75 mg/kg per day (p=0.05) and MMP-3 at all doses tested (p≤0.02). The serum level of CTX-II was reduced (p≤0.04) by SrRan at 16 weeks in dogs treated with 50 and 75 mg/kg per day.


CONCLUSIONS
This study is the first to demonstrate in vivo in an animal model that SrRan reduced the progression of osteoarthritis structural changes. The inhibition of several key proteases as well as IL-1β may have contributed to the beneficial effect of SrRan.
Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec, Canada H2L 4M1. dr@jppelletier.ca
Jean-Pierre
JP
Pelletier
Mohit
M
Kapoor
Hassan
H
Fahmi
Daniel
D
Lajeunesse
Alexia
A
Blesius
Juliette
J
Maillet
Johanne
J
Martel-Pelletier
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D053583:Interleukin-1beta / Q000096:biosynthesis; D009942:Organometallic Compounds / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D018501:Antirheumatic Agents; D053583:Interleukin-1beta; D009942:Organometallic Compounds; D013876:Thiophenes; C081587:strontium ranelate; D010447:Peptide Hydrolases