Abstract
Purpose: It is generally recognized that osteoarthritis (OA) is a complex multifactorial disease process involving articular cartilage, subchondral bone, tendons, and synovium. Alendronate (ALN) inhibits bone loss and increases bone mineralization. The aim of this study was to examine whether ALN altered cartilage degeneration and periarticular bone quality in the rabbit anterior cruciate ligament transection (ACLT) model of OA. Moreover, the mechanism responsible for ALN effects on cartilage was investigated using immunohistochemical analysis. Methods: Skeletally matured, thirty female Japanese white rabbits underwent an ACLT on the left knee and a sham operation on the right knee. Fifteen rabbits then received weekly subcutaneous injections of ALN (0.14 mg/kg) beginning on the day of surgery and 15 rabbits received subcutaneous injections of saline according to the same schedule. Five animals from each group were sacrificed 2, 4 or 12 weeks after surgery. Sixty operated knees of 30 rabbits were divided into four groups. The right and left knees of rabbits that received saline treatment (control [cont] group) and those of rabbits that received ALN treatment were designated cont/sham, cont/ACLT, ALN/sham and ALN/ACLT, respectively. Assays for serum N-telopeptide of type I collagen (NTX) level were performed before treatment of ALN and after sacrificed. The distal femur and the proximal tibia were scanned by micro-computed tomography (mCT) to quantify the bone volume ratio. Macroscopic view, histological score, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemical index for matrix metalloproteinase 13 (MMP13), interleukin-1b (IL-1b), type X collagen (COLX), vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kB ligand (RANKL) were evaluated for each group. Results: Serum NTX level was suppressed by ALN at 4 weeks post-surgery. Twelve weeks after the surgery, the cont/ACLT group had more periarticular trabecular bone loss and osteophyte formation than the cont/ sham group. However, the ALN/ACLT group maintained bone formation in a manner similar to that of the ALN/sham group. The expression of TRAPpositive osteoclasts in subchondral bone was prevented by ALN. Macroscopic and histological evaluation revealed that the cont/ACLT group had significantly worse cartilage damage than the cont/sham group 12 weeks after the surgery, but the ALN/ACLT group had mild cartilage degeneration compared with that of the ALN/sham group. Protein expression levels of MMP13, IL-1b, COLX, VEGF and RANKL in the cartilage were suppressed in the ALN/ACLT group compared with the cont/ACLT group. Conclusions: The effect of ALN as a potent inhibitor of osteoclastic bone resorption was verified by suppressed serum NTX level, increased subchondral bone volume and inhibited TRAP-positive osteoclasts expression. Macroscopically and histologically, ALN had a chondroprotective effect in our experimental rabbit model of OA. Immunohistochemical analysis showed that ALN suppressed the expression of MMP13, IL-1b, COLX, VEGF and RANKL in OA cartilage. We propose that ALN protects normal joint loading by preserving subchondral bone quality and thereby conserves articular cartilage by inhibiting the expression of MMP13, IL-1b, COLX, VEGF and RANKL. Our results suggest therapeutic roles for ALN in inhibiting subchondral bone loss in the early stage of OA, in protecting cartilage against degeneration and in preserving long-term joint function.
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