Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development

Abstract

Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of five WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90 + /CD105 + stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A, and DKK3 was the most marked. In general, we found that canonical Wnt/b-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2 + pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, whereas dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes

“…Cellular functions of Vangl2 have been explored for more than two decades since Vangl2/Stbm was first identified in Drosophila [24]. A previous study in human revealed that the expression of Vangl2 increased in the OA synovium [17]. Thus, our finding that Vangl2 was significantly increased in OA chondrocytes raised the question of whether Vangl2 plays a role in OA progression.…”

“…Van Gogh-like 2 (Vangl2) is a core PCP component that regulates Wnt/PCP signaling [12][13][14][15]. Recently, evidence has accumulated that the pathogenesis of OA is associated with abnormal activation of Wnt/PCP pathway, which regulates the expression of MMPs and cartilage-related genes [9,10,[16][17][18]. Notably, previous research suggested that Vangl2 plays a crucial role in cartilage development and disease.…”

Silencing of Vangl2 Attenuates the Inflammation Promoted by Wnt5a via MAPK and NF-κB Pathway in Chondrocytes.

“…Cellular functions of Vangl2 have been explored for more than two decades since Vangl2/Stbm was rst identi ed in Drosophila [24]. A previous study in human revealed that the expression of Vangl2 increased in the OA synovium [17]. Our nding that Vangl2 was also signi cantly increased in OA chondrocytes raised the question of whether Vangl2 plays a role in OA progression.…”

Silencing of Vangl2 attenuates the inflammation promoted by Wnt5a via MAPK and NF-κB pathway in chondrocytes.

“…Cellular functions of Vangl2 have been explored for more than two decades since Vangl2/Stbm was rst identi ed in Drosophila [24]. A previous study in human revealed that the expression of Vangl2 increased in the OA synovium [17]. Thus, our nding that Vangl2 was signi cantly increased in OA chondrocytes raised the question of whether Vangl2 plays a role in OA progression.…”