Integrin αVβ3 Signaling in the Progression of Osteoarthritis Induced by Excessive Mechanical Stress

Abstract

Osteoarthritis (OA) is believed to be linked with cartilage degeneration, subchondral bone sclerosis, and synovial inflammation that lead to joint failure, and yet treatment that can effectively reverse the pathological process of the disease still not exists. Recent evidence suggests excessive mechanical stress (eMS) as an essential role in the pathogenesis of OA. Increased levels of integrin αVβ3 have been detected in osteoarthritic cartilage and were previously implicated in OA pathogenesis. However, the role of integrin αVβ3 in the process of eMS-induced OA remains unclear. Here, histologic and proteomic analyses of osteoarthritic cartilage in a rat destabilization of the medial meniscus model demonstrated elevated expression of integrin αVβ3 as well as more serious cartilage degeneration in the medial weight-bearing area. Furthermore, results of in vitro study demonstrated that eMS led to a significant increase of integrin αVβ3 expression and phosphorylation of downstream signaling molecules such as FAK and ERK, as well as upregulated expressions of inflammatory and degradative mediators. In addition, we found that inhibition of integrin αVβ3 could alleviate chondrocyte inflammation triggered by eMS both in vivo and in vitro. Our findings suggest a central role for upregulation of integrin αVβ3 signaling in OA pathogenesis and demonstrate that activation of integrin αVβ3 signaling in cartilage contributes to inflammation and joint destruction in eMS-induced OA. Taken together, our data presented here provide a possibility for targeting integrin αVβ3 signaling pathway as a disease-modifying therapy.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

“…The diagnosis- and treatment-integrated micelle ERMs@siM13 was designed based on the following considerations. In the MMP13-deficient region, EPs are expected to shield cRGD ligands through the PEG layer, protecting the micelles from nonspecific uptake by healthy chondrocytes that also express αvβ3 integrin at a certain level [ 27 , 28 , [39] , [40] , [41] ]. Meanwhile, the fluorescence signal of Cy5 in EPs is quenched by BHQ3 [ 19 ].…”

“…Normal and diseased chondrocytes express αvβ3 integrins [ 27 , 28 ], mediating cRGD-modified nanovehicles' internalization [ [29] , [30] , [31] ]. However, surrounding the MMP13-deficient healthy chondrocytes, the ERMs’ cRGD ligands were shielded by EP-derived PEG layer, showing significantly lower cellular uptake than cRGD-exposed RMs ( Fig.…”

“…Encapsulation with nanovehicles has been revealed to prolong the articular retention of payloads [ 11 ]. Healthy and diseased chondrocytes universally express αvβ3 integrins [ 27 , 28 ], which can mediate the cell internalization of Arg-Gly-Asp (RGD)-modified nanovehicles via ligand-receptor interaction [ [29] , [30] , [31] ]. Modification with the flexible and hydrophilic long PEG chains can shield the ligands on the nanovehicle surface, protecting the nanovehicles from nonspecific uptake [ 32 , 33 ].…”

Research progress on the regulatory mechanism of integrin‐mediated mechanical stress in cells involved in bone metabolism

“…Researchers 11 have found that cilengitide (integrin receptor antagonist) inhibits the expression of inflammation‐related genes such as IL‐1β, TNF‐α, MMP‐3 and MMP‐13 induced by excessive mechanical stress (10% elongation rate, 0.5 Hz and 3 h) and suppresses the phosphorylation levels of integrin downstream‐related molecules such as FAK, ERK, JNK and p38; these results suggest that excessive mechanical stress can activate integrins on the surface of chondrocytes and upregulate the expression of inflammatory‐related factors through the phosphorylation of FAK and MAPKs, thereby inducing cartilage inflammation. Through histological and proteomic analyses of osteoarthritic cartilage in a destabilized medial meniscus rat model and in vitro findings, SONG et al 103 . demonstrated that excessive mechanical stress (15 V, 2 Hz) led to significantly increased integrin αVβ3 expression, enhanced the phosphorylation of downstream signalling molecules, such as FAK and ERK, and upregulated the expression of inflammation‐related proteins, such as MMP‐9, 13 and Adamts‐5; the inhibition of integrin αVβ3 attenuated chondrocyte inflammation induced by excessive mechanical stress in vivo and in vitro.…”

“…Through histological and proteomic analyses of osteoarthritic cartilage in a destabilized medial meniscus rat model and in vitro findings, SONG et al. 103 demonstrated that excessive mechanical stress (15 V, 2 Hz) led to significantly increased integrin αVβ3 expression, enhanced the phosphorylation of downstream signalling molecules, such as FAK and ERK, and upregulated the expression of inflammation‐related proteins, such as MMP‐9, 13 and Adamts‐5; the inhibition of integrin αVβ3 attenuated chondrocyte inflammation induced by excessive mechanical stress in vivo and in vitro.…”