Captopril, an angiotensin-converting enzyme inhibitor, possesses chondroprotective efficacy in a rat model of osteoarthritis through suppression local renin-angiotensin system

Abstract

Objective: A local tissue-specific renin-angiotensin system (local RAS) has emerged as a regulator of cartilage development and homeostasis. However, no report has described the chondroprotective efficacy of RAS inhibitor. Therefore, we studied the pharmacological function of captopril on hypertrophic differentiation of chondrocytes, cartilaginous degeneration and RAS components expression in a rat model of osteoarthritis (OA).

Methods: OA was surgically induced in the right knee of male rats. Animal groups included age matched sham control (sham group), OA placebo (OA group), and OA treated with captopril (CAP group). Eight weeks after the induction of OA, the tibias were isolated and the sagittal sections were stained with Safranin O and Masson-Trichrome. The mRNA and protein expression of RAS components were measured by qRT-PCR and western blotting respectively.

Results: The thickness of articular cartilage was reduced in the proximal tibia of the OA group, and decreased thickness of articular cartilage of the OA mice was effectively reversed by captopril treatment. Histological analyses revealed remarkable chondrocytes abnormality in OA rats, which were characterized by a marked expansion of hypertrophic zone and inhibition of proliferative zone of chondrocytes in the epiphyseal growth plate of tibia. However, captopril-treated could reverse chondrocytes abnormality in OA rats. Furthermore, the mRNA and protein expression of RAS components, renin, ACE, Ang II AT1R were upregulated in the proximal tibia of OA rats, however, the AT2R expression was suppressed. Intriguingly, captopril-treated could inhibit the activation of RAS in OA rats.

Conclusions: The present study demonstrated that captopril could attenuate OA-induced osteoarticular injury, at least partially, through suppression local RAS.

Keywords: Osteoarthritis; captopril; chondrocytes; renin-angiotensin system.

Figure 1

Images of safranin O staining of the sagittal knee joint section. Samples eight weeks after induction of osteoarthritis, the tibias were stained by safranin O staining (A). The thickness of articular cartilage is shown by black arrows (magnification, × 50) and the width of the articular cartilage was quantified (B). Graphs showed histological scores of tibias for progression of osteoarthritis (C). Values are expressed as mean ± SEM, n = 6 in each group. *P < 0.05, versus Sham group; #P < 0.05, versus OA group.

Figure 2

The chondrocyte zone at growth plate was shown in sham, OA and CAP group, and it was visually separated into two areas, proliferative zone (PZ) and hypertrophic zone (HZ) (A). The width of the PZ and HZ was quantified (B). Values are expressed as mean ± SEM, n = 6 in each group. *P < 0.05, versus Sham group; #P < 0.05, versus OA group.

Figure 3

The expression of renin and renin-receptor in the proximal tibias. The mRNA expression of renin and renin-receptor was measured by qRT-PCR (A). The protein expression of renin was measured by western blotting (B). Values are expressed as mean ± SEM, n = 6 in each group. *P < 0.05, versus Sham group; #P < 0.05, versus OA group.

Figure 4

The expression of ACE and Ang II in the proximal tibias. The mRNA (A) and protein (B) expression of ACE were measured by qRT-PCR and western blotting respectively. The AGT mRNA (C) and Ang II protein (D) expression were measured by qRT-PCR and western blotting respectively. Values are expressed as mean ± SEM, n = 6 in each group. *P < 0.05, versus Sham group; #P < 0.05, versus OA group.

Figure 5

The expression of AT1R and AT2R in the proximal tibias. The mRNA (A) and protein (B) expression of AT1R were measured by qRT-PCR and western blotting respectively. The mRNA (C) and protein (D) expression of AT2R were measured by qRT-PCR and western blotting respectively. Values are expressed as mean ± SEM, n = 6 in each group. *P < 0.05, versus Sham group; #P < 0.05, versus OA group.