Effects of HDAC4 on IL-1b-Induced Matrix Metalloproteinase Expression Regulated Partially Through the WNT3A/b-Catenin Pathway
Osteoarthritis (OA) is one of the most common degenerative joint disorders, characterized by the degeneration of articular cartilage and the loss of joint function. The temporomandibular joint (TMJ), a synovial joint crucial for craniofacial growth and function, is also susceptible to OA. The maintenance of cartilage homeostasis is essential for its structural integrity, and the balance between matrix destruction and repair is regulated by the catabolic and anabolic activities of chondrocytes. Although the specific mechanisms of OA remain unclear, growing evidence suggests that catabolic alterations and inflammation play critical roles in its development. Proinflammatory cytokines such as interleukin-1 beta (IL-1b) are key mediators in OA pathophysiology, leading to chondrocyte apoptosis and extracellular matrix (ECM) degradation. Specifically, IL-1b upregulates matrix metalloproteinases (MMPs), including MMP3 and MMP13, which degrade type II collagen and aggrecan, the major components of the cartilage matrix. Therefore, inhibiting IL-1b-induced catabolic metabolism and inflammatory responses could delay OA progression.
Epigenetic alterations, particularly involving histone deacetylases (HDACs), have been implicated in OA pathogenesis. HDAC4, a class II HDAC, plays a crucial role in chondrocyte hypertrophy and bone formation. HDAC4-null mice exhibit aberrant chondrocyte hypertrophy and premature ossification, while HDAC4 overexpression represses chondrocyte hypertrophy in vitro. Given that hypertrophic chondrocytes express high levels of MMP3 and MMP13, it was hypothesized that HDAC4 might influence IL-1b-induced MMP expression. Additionally, the WNT/b-catenin signaling pathway, which regulates cartilage homeostasis, has been linked to OA. WNT3A, a major activator of canonical WNT/b-catenin signaling, and b-catenin are upregulated in OA models. IL-1b can activate WNT/b-catenin signaling in chondrocytes, but the relationship between WNT signaling and HDAC4 in TMJ OA remains unclear. This study aimed to explore the effects of HDAC4 on IL-1b-induced ECM degradation and its regulation through the WNT3A/b-catenin pathway.
Primary chondrocytes (CC) were isolated from the TMJ condyles of 4-week-old Wistar rats, and human chondrosarcoma cells (SW1353) were cultured in vitro. To establish an OA model, cells were treated with IL-1b, and HDAC4 levels were assayed using Western blotting. HDAC4 expression in SW1353 cells was silenced using small interfering RNA (siRNA) to investigate its effect on MMP3 and MMP13 levels. HDAC4 was also overexpressed in SW1353 cells using plasmid transfection, and the levels of MMP3 and MMP13 were measured. The activation of the WNT3A/b-catenin pathway was assessed by observing b-catenin translocation into the nucleus using immunofluorescence staining. Additionally, the effects of WNT3A and glycogen synthase kinase 3 beta (GSK3b) on HDAC4 levels were evaluated.
IL-1b treatment downregulated HDAC4 levels in both primary chondrocytes and SW1353 cells in a time- and dose-dependent manner. Correspondingly, MMP3 and MMP13 levels increased with IL-1b treatment. HDAC4 knockdown in SW1353 cells further elevated MMP3 and MMP13 levels, indicating that HDAC4 silencing enhances IL-1b-induced ECM degradation. Conversely, HDAC4 overexpression inhibited IL-1b-induced increases in MMP3 and MMP13 levels, suggesting a protective role of HDAC4 in cartilage homeostasis. These findings demonstrate that HDAC4 exerts an inhibitory effect on IL-1b-induced ECM degradation.
The WNT3A/b-catenin pathway was activated by IL-1b, as evidenced by the upregulation of WNT3A and the translocation of b-catenin into the nucleus. WNT3A treatment downregulated HDAC4 levels in SW1353 cells in a time- and dose-dependent manner, while also increasing MMP3 and MMP13 expression. Overexpression of GSK3b, an inhibitor of the WNT/b-catenin pathway, rescued IL-1b-induced downregulation of HDAC4, further confirming the involvement of the WNT3A/b-catenin pathway in regulating HDAC4 expression.
These results suggest that HDAC4 plays a protective role in IL-1b-induced ECM degradation by inhibiting MMP3 and MMP13 expression. The WNT3A/b-catenin pathway partially regulates HDAC4, as WNT3A downregulates HDAC4 levels, while GSK3b overexpression restores them. This study provides insights into the molecular mechanisms underlying OA pathogenesis and highlights the potential therapeutic value of targeting HDAC4 and the WNT3A/b-catenin pathway in OA treatment.
In summary, HDAC4 inhibits IL-1b-induced ECM degradation by downregulating MMP3 and MMP13 expression, and this effect is partially mediated by the WNT3A/b-catenin pathway. Future studies should further investigate the role of HDAC4 in OA progression and explore its interactions with other signaling pathways. Animal experiments are necessary to confirm these findings and to evaluate the therapeutic potential of modulating HDAC4 and WNT3A/b-catenin signaling in OA.
doi.org/10.1097/CM9.0000000000001470
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