Cyclic compressive loading activates angiotensin II type 1 receptor in articular chondrocytes and stimulates hypertrophic differentiation through a G‐protein‐dependent pathway

Abstract

Angiotensin II type 1 receptor ( AT 1R) appears to have a mechanosensing function in a number of cell types. The purpose of this study was to examine whether AT 1R expressed in articular chondrocytes is involved in osteoarthritis (OA) progression in vivo and whether cyclic compressive loading activates the AT 1R and stimulates hypertrophic differentiation of chondrocytes in vitro . The relationships between the modified Mankin score for cartilage degeneration and the expression of AT 1R and type X collagen (Col X) were studied in mouse knees with OA induced using the destabilization‐of‐medial‐meniscus model. Cyclic compressive loads were applied to cultured bovine articular chondrocytes in three‐dimensional agarose scaffolds. Expression of Col X and runt‐related transcription factor 2 (Runx2) was analyzed using RT‐PCR and western blotting. We dissected the downstream pathway for intracellular signal transductions of AT 1R including G‐protein‐dependent and G‐protein‐independent pathways. Positive significant correlations between the Mankin score and the rate of AT 1R‐immunopositive cells and between the rates of AT 1R and Col X expression were noted. The expression of Col X and Runx2 was increased by compressive loading but suppressed by addition of olmesartan, an Ang II receptor blocker, to the agarose scaffolds. Compressive loading upregulated the phosphorylation of c‐Jun N‐terminal kinase ( JNK ), Src, and STAT 1, but olmesartan significantly suppressed only JNK phosphorylation. We conclude that AT 1R expressed by articular chondrocytes may be involved in OA progression in vivo . Mechanical stress can activate AT 1R and stimulate hypertrophic differentiation of chondrocytes through the G‐protein‐dependent pathway. AT 1R has a mechanosensing function in chondrocytes and may be a new therapeutic target in OA .

Roles of CCN2 as a mechano-sensing regulator of chondrocyte differentiation

“…However, a recent study found agonist-independent mechanical-induced AT 1 R activation [30] , [47] . Several groups showed that the expression of AT 1 R and AT 2 R genes is detectable in chondrocytes [82] , [83] , and we have shown that CCN2 is increased at mRNA and protein levels by treatment with ANGII (Nishida et al, unpublished data). Additionally, we have also shown that ANGII-induced phosphorylation of p38 is decreased by pretreatment with losartan, which is a specific blocker of AT 1 R (Nishida et al, unpublished data).…”

Cartilage tissue engineering for obesity-induced osteoarthritis: Physiology, challenges, and future prospects

“…subjected bovine cartilage chondrocyte-seeded agarose constructs to cyclic compressive load. Results showed that compressive loading up-regulated the expression of type X collagen and runt-related transcription factor 2, indicating the increased population of hypertrophic differentiated chondrocytes in the cartilage [ 93 ]. Activation of phosphorylation of c-Jun N-terminal kinase (JNK), Src, and STAT1 was also observed in chondrocytes subjected to altered functional load [ 93 ].…”

“…Results showed that compressive loading up-regulated the expression of type X collagen and runt-related transcription factor 2, indicating the increased population of hypertrophic differentiated chondrocytes in the cartilage [ 93 ]. Activation of phosphorylation of c-Jun N-terminal kinase (JNK), Src, and STAT1 was also observed in chondrocytes subjected to altered functional load [ 93 ]. Abnormal mechanical loading alters cellular biochemical activities through stimulation of mechanoreceptors on the surface of chondrocytes that regulate cartilage remodelling and turnover, eventually resulting in cartilage breakdown [ 94 ].…”

Synovial fluid peptidase activity as a biomarker for knee osteoarthritis clinical progression

“… 15 Angiotensin II is a known potent proinflammatory mediator, 16 and angiotensin receptor blockers show anti-inflammatory effects in animal models of arthritis. 17 Further, articular chondrocyte angiotensin II type 1 receptor was implicated in KOA progression in a mechanical stress mouse model 18 and activation of the renin-angiotensin system might be involved in the pathogenesis of this condition. 12 Nonetheless, the association between angiotensin-converting enzyme and KOA remains controversial.…”