Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms22179204
Keywords
angiotensin II; cellular communication network factor 2 (CCN2); renin-angiotensin system (RAS); losartan; angiotensin II type I receptor (AT(1)R)
Funding
- KAKENHI grants from the Japan Society for the Promotion of Sciences, Japan [JP17K11641, JP20K09889, JP21H03105, JP19H03817, JP20K20611]
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This study revealed that angiotensin II has negative effects on chondrocyte metabolism, while AT(1)R blockade can mitigate these effects, potentially reducing chondrocyte degeneration. Additionally, ANG II regulates age-related cartilage degeneration through the ANG II-AT(1)R axis.
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 (AT(1)R) and type 2 (AT(2)R), 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 AT(1)R 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 AT(1)R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT(1)R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT(1)R-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-AT(1)R axis.
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