Aliskiren has chondroprotective efficacy in a rat model of osteoarthritis through suppression of the local renin-angiotensin system

Abstract

The local renin-angiotensin system (RAS) has been reported to have an important role in the pathogenesis and progression of metabolic bone diseases, including osteoarthritis (OA). Aliskiren is the first in a new class of orally effective direct renin inhibitors and is approved for the treatment of hypertension in humans. However, its efficacy in patients with OA is unknown. A rat model of OA was induced to investigate the potential efficacy of aliskiren. Effects of aliskiren on the cartilage structure were detected by safranin O staining and its effects on the widths of the proliferation zone and hypertrophic zone (HZ) of chondrocytes were analyzed by Masson's staining. Tartate-resistant acid phosphatase staining was used to evaluate the effects of aliskiren on osteoclasts in the chondrocytes. Relative histological analyses were performed. Additionally, the expression levels of factors associated with osteoclast differentiation (receptor activator of nuclear factor κB ligand and osteoprotegerin), articular cartilage destruction [tumor necrosis factor-α (TNF-α) and matrix metalloproteinase 9] and osteoblast differentiation [runt related transcription factor 2 (Runx2)], along with RAS components (renin, renin-receptor, angiotensin type 1 receptor (AT1R), AT2R, angiotensin converting enzyme (ACE) and angiotensin II (Ang II)] were detected in samples from the proximal tibias. Aliskiren did not fully suppress the inflammatory reaction in OA model animals and had marginal regulatory effects on biochemical bone markers induced by OA. However, aliskiren attenuated cartilage destruction, abnormal cartilage cellularity and the expansion of the HZ of chondrocytes, and significantly attenuated the expression of interleukin-1, TNF-α, Runx2 and procollagen type I N-terminal propeptide. These chondroprotective properties were accompanied by reductions in the levels of RAS components (renin, Ang II, ACE and AT1R), indicating that aliskiren exerts multiple effects of on bone formation, osteoblast differentiation and articular cartilage protection via the RAS. OA activates the local bone RAS, inhibits bone formation and stimulates bone resorption. Aliskiren, a renin inhibitor, demonstrated chondroprotective efficacy in a rat model of OA through suppression of the local RAS.