Abstract
The renin–angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II–AT1R axis.
Highlights
Obesity is a risk factor for osteoarthritis (OA) [1]
Because it was reported that angiotensin II (ANG II) is one of the peptide hormones induced by aging and obesity [3] and that chondrocytes express it two specific receptors, angiotensin II receptor type 1 (AT1R) and type 2 (AT2R) [4], we focused on ANG II functions in chondrocytes in this study
Angiotensin I (ANG I), which is the precursor of ANG II, is formed by the cleavage of angiotensinogen produced in the liver by renin expressed in the kidney, and ANG I is cleaved by angiotensin-converting enzyme 1 (ACE1) to form ANG II [5]
Summary
Obesity is a risk factor for osteoarthritis (OA) [1]. Overloading the knee joints due to obesity is considered a significant risk factor for the induction of articular cartilage degradation [1]. Angiotensin I (ANG I), which is the precursor of ANG II, is formed by the cleavage of angiotensinogen produced in the liver by renin expressed in the kidney, and ANG I is cleaved by angiotensin-converting enzyme 1 (ACE1) to form ANG II [5] This classical system is called the systemic renin–angiotensin system (RAS) and encompasses the multiple organs involved in forming ANG II [5]. A recent study demonstrated that AT1R blockade reduced the chronic kidney disease-induced deterioration of bone [17] These findings suggest that ANG II produced by the local RAS may be involved in the regulation of cartilage and bone metabolism. In this study, we analyzed the effects of ANG II and AT1R blockade on the proliferation, differentiation, and functional disorder of chondrocytes and explored the involvement of ANG II in the production of CCN2 in chondrocytes
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