Endothelial Stat3 activation promotes osteoarthritis development

Abstract

The mechanism of the balance between subchondral angiogenesis and articular damage within osteoarthritis (OA) progression remains a mystery. However, the lack of specific drugs leads to limited clinical treatment options for OA, frequently failing to prevent eventual joint destruction in patients. Increasing evidence suggests that subchondral bone angiogenesis precedes cartilage injury, while proliferating endothelial cells (ECs) induce abnormal bone formation. Signal transducer and activator of transcription 3 (Stat3) is triggered by multiple cytokines in the OA microenvironment. Here, we observed elevated Stat3 activation in subchondral bone H‐type vessels. Endothelial Stat3 activation will lead to stronger cell proliferation, migration and angiogenesis by simulating ECs in OA. In contrast, either Stat3 activation inhibition or knockdown of Stat3 expression could relieve such alterations. More interestingly, blocking Stat3 in ECs alleviated angiogenesis‐mediated osteogenic differentiation and chondrocyte lesions. Stat3 inhibitor reversed surgically induced subchondral bone H‐type vessel hyperplasia in vivo, significantly downregulating vessel volume and vessel number. Due to the reduced angiogenesis, subchondral bone deterioration and cartilage loss were alleviated. Overall, our data suggest that endothelial Stat3 activation is an essential trigger for OA development. Therefore, targeted Stat3 blockade is a novel promising therapeutic regimen for OA.

Synovial Fluid from Patients with Osteoarthritis Shows Different Inflammatory Features Depending on the Presence of Calcium Pyrophosphate Crystals

“…Although the levels of the growth factor did not differ among the two populations of patients, we found higher concentrations of VEGF in the early stages of the whole OA patients (KL degree 1–2). This might support the concept that subchondral bone angiogenesis precedes cartilage injury [ 20 ]. Furthermore, VEGF was found to correlate with mononuclear cell, an effective source of this growth factor.…”

“…Considering the recent observation on the activation of vascular endothelial cells in OA synovial fibrosis [ 19 ] and their role in subchondral bone angiogenesis [ 20 ], we sought to determine VEGF in SF samples, along with a well-known degrading enzyme, MMP-1, associated with vascular remodelling and induced by VEGF itself [ 21 ]. Although the levels of the growth factor did not differ among the two populations of patients, we found higher concentrations of VEGF in the early stages of the whole OA patients (KL degree 1–2).…”

Mechanisms of vascular invasion after cartilage injury and potential engineering cartilage treatment strategies

“…STAT3 is a common downstream transcriptional activator in response to a variety of cytokines and is a key transcription factor regulating angiogenesis in various diseases and tumors 88,89 . Recent studies have demonstrated that in the inflammatory microenvironment of OA, activated STAT3 promotes the proliferative migration of ECs and contributes to the abnormal proliferation of H‐vessels, as well as the osteogenic differentiation of BMSCs and the extracellular matrix breakdown of chondrocytes, which are key factors in the process of OA 90 …”

Cyaonoside A-loaded composite hydrogel microspheres to treat osteoarthritis by relieving chondrocyte inflammation

“…In the pathogenesis of OA, abnormal osteophytes and bone remodeling of the subchondral bone were essential in determining the severity of the joint injury. [63][64][65] Severe ossification of the subchondral bone in OA rats resulted in the loss of normal mechanical structures (Fig. 7A).…”