Suppression of cartilage degeneration by intra-articular injection of heparan sulfate 6-O endosulfatase in a mouse osteoarthritis model.
We previously reported that heparan sulfate 6-O endosulfatases (Sulfs) were expressed in articular cartilage, and that the Sulf-1 knockout mouse developed severe knee osteoarthritis. In this study, we hypothesised that intra-articular injection of Sulf-1 would prevent cartilage degeneration. After confirming that 1 mg/ml Sulf-1 did not induce ATDC5 cell death in vitro, gene expression of type II collagen and matrix metalloproteinase (MMP)-13 in the presence of Sulf-1 (1 100 ng/ml) were determined by quantitative real-time polymerase chain reaction. Sulf-1 was also injected intra-articularly into mice following surgical destabilisation of the medial meniscus to produce a model of osteoarthritis, and cartilage degeneration was evaluated by safranin O and MMP-13 staining. We also investigated fibroblast growth factor 2 (FGF2)/extracellular signal-regulated kinase (Erk) cell signalling by western blotting. Exposure to Sulf-1 in vitro increased type II collagen expression and decreased MMP-13 expression in a concentration-dependent manner. Sulf-1 injection into the mouse osteoarthritic knee significantly suppressed glycosaminoglycan loss and MMP-13 expression. Erk1/2 signalling pathway activation was significantly reduced by Sulf-1 and FGF2. These findings indicate that Sulf-1 prevents cartilage degeneration by suppressing MMP-13 via an effect on FGF2/Erk1/2 signalling.
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan. ort182@osaka-med.ac.jp.
Shuhei
S
Otsuki
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan.
Tomohiko
T
Murakami
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan.
Yoshinori
Y
Okamoto
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan.
Yoshiaki
Y
Hoshiyama
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan.
Shuhei
S
Oda
Department of Orthopedic Surgery, Osaka Medical College, Osaka, Japan.
Masashi
M
Neo
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007150:Immunohistochemistry; D007270:Injections, Intra-Articular; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology*; D015238:Sulfotransferases / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*
D024043:Collagen Type II; D016222:Fibroblast Growth Factor 2; C486773:Sulf1 protein, mouse; D015238:Sulfotransferases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse