HMGB1 palys an important role in the pathogenesis of osteoarthritis

HMGB1 palys an important role in the pathogenesis of osteoarthritis

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Credit:DOI:https://doi.org/10.1186/s12891-023-06208-0.The correlation between the synovial fluid level of HMGB1 and the severity of temporomandibular joint osteoarthritis (TMJOA)

Osteoarthritis (OA) is a clinical disease that causes pain and dysfunction in the affected joints. The pathogenic factors of OA are complex, including metabolic, epigenetic and genetic factors. Studies have shown that chronic low-grade inflammation caused by programmed necrosis of chondrocytes plays an important role in the pathogenesis of OA. Among them, high-mobility group box 1 protein B1(HMGB1) belonging to danger induced molecular patterns (DAMPs) in programmed necrosis plays a central role in the immune-inflammatory response. HMGB1 binds to the intrinsic immune pattern recognition receptor TLR4 and activates intracellular signaling pathways, leading to programmed chondrocyte death, release of inflammatory factors and exacerbation of the inflammatory cascade in synovial tissues of articular cartilage, which is manifested as OA cartilage degeneration and synovitis [1].

High mobility group protein (HMGP) is a non-histone component that binds to chromosomes and includes three family members: high mobility group protein A (HMGA), high mobility group protein B (HMGB) and high mobility group protein N (HMGN) [2]. HMGB contains three members: HMGB1, HMGB2 and HMGB3, which are widely found in the nucleus of monocyte macrophages and are closely related to the development of immunoinflammatory diseases. The human HMGB1 gene, localized in chromosome 13q12, contains 219 amino acid residues and consists of three DNA domains: the A-box, the B-box and an acidic C-tail. Among them, HMG A-box (9-85 amino acids) is at the N-terminus, which is the region of negative feedback inhibition, and C-tail (186-215 amino acids) is at the carboxyl-terminus, which regulates the interaction between HMGB1 and chromosomes by increasing the binding capacity of DNA and HMGB1. Box-A binds to C-tail and enhances its anti-inflammatory activity. HMG box B (89-162 amino acids) is located between the two, which is a functional domain that activates the inflammatory response, while A-box can antagonize the inflammatory response caused by box-B [3].

Chronic low-grade inflammation and imbalance of immune regulation in joint tissues are important mechanisms for the development of OA. When inflammation occurs in the early stages of the body, small amounts of HMGB1 are released to mediate inflammatory signaling and programmed necrosis of chondrocytes through pattern recognition receptors [4]. As the inflammatory cycle amplifies, the level of HMGB1 increases, which further drives the release of inflammatory cytokines and interacts with a variety of cytokines and chemokines to cause inflammatory injury in cartilage and synovial tissue [5]. Therefore, HMGB1 serves as a central molecule in the inflammatory waterfall cascade of OA, and inhibition of HMGB1 expression regulates the inflammatory signaling pathway and expression of inflammatory factors for the treatment of OA.

HMGB1 binds to TLR4 on the upper surface of macrophages, synoviocytes and articular chondrocytes and activates NF-κB expression in the nucleus of chondrocytes, which secretes matrix-degrading enzymes (MMPs and ADAMTs) and inhibits the synthesis of aggregin and type II collagen. The synthesis of chondrocyte ECM was reduced, and chondrocyte ECM homeostasis was disrupted, which led to an imbalance in the metabolic homeostasis of articular chondrocytes and extracellular matrix. In addition, the apoptosis of chondrocytes promoted the increased release of HMGB1 from chondrocytes, which further strengthened the chronic low-grade inflammatory cycle in chondrocytes, and accelerated the apoptosis of chondrocytes and extracellular matrix decomposition[6].

Reference

  1. Li, C., Ouyang, Z., Huang, Y., Lin, S., Li, S., Xu, J., Liu, T., Wu, J., Guo, P., Chen, Z., Wu, H., & Ding, Y. (2023). NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages. Arthritis research & therapy, 25(1), 249.

  2. Shao, B., Xu, Y., Jia, M., Li, C. X., & Gong, Z. C. (2023). Association of HMGB1 levels in synovial fluid with the severity of temporomandibular joint osteoarthritis. BMC musculoskeletal disorders, 24(1), 183.

  3. Colavita, L., Ciprandi, G., Salpietro, A., & Cuppari, C. (2020). HMGB1: A pleiotropic activity. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 31 Suppl 26(Suppl 26), 63–65.

  4. Wenzhao, L., Jiangdong, N., Deye, S., Muliang, D., Junjie, W., Xianzhe, H., Mingming, Y., & Jun, H. (2019). Dual regulatory roles of HMGB1 in inflammatory reaction of chondrocyte cells and mice. Cell cycle (Georgetown, Tex.), 18(18), 2268–2280.

  5. Li, W., Tao, C., Mao, M., & Zhu, K. (2023). The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis. Acta biochimica et biophysica Sinica, 55(5), 818–830.

  6. Xiong, T., Huang, S., Wang, X., Shi, Y., He, J., Yuan, Y., Wang, R., Gu, H., & Liu, L. (2024). n-3 polyunsaturated fatty acids alleviate the progression of obesity-related osteoarthritis and protect cartilage through inhibiting the HMGB1-RAGE/TLR4 signaling pathway. International immunopharmacology, 128, 111498.