benniegeorge authored 10 months ago

With the deepening of the pathological process and molecular mechanism of intervertebral disc degeneration, the application of biological methods to intervene the degeneration process of the intervertebral disc provides a new idea for the treatment of intervertebral disc degeneration. The most important biochemical change in the early stage of ECM degeneration of the disc nucleus is the loss of proteoglycans.

Cong et al. studied 197 Han Chinese in northern China, including 70 patients with clinically symptomatic lumbar disc herniation (LDH). It was found that the ACAN content in normal human intervertebral disc tissue was significantly higher than that in the case group, while the short sequence VNTR allele expressed less ACAN. Le Maitre CL et al. have shown that increased expression of aggrecanase 1 in the nucleus pulposus cells of the intervertebral disc leads to degeneration of the intervertebral disc. Perera et al. evaluated the association of single nucleotide variants (SNVs) of the candidate genes of the ACAN metabolic pathway with the severity of lumbar disc herniation in patients with chronic mechanical low back pain. This study showed that SNVs of ACAN and their haplotypes are associated with the severity of lumbar disc herniation.

Because chondrocytes themselves may produce various cytokines or inflammatory synovial infiltration, and osteoarthritis has increased articular cartilage catabolism. Interleukin1 and TNFα not only stimulate the production of protease but also down regulate the production of ACAN. These inflammatory factors are related to the production of ACAN and MMPs, which reduce the ACAN core protein.

In the study of osteoarthritis, Aggrecanase 1 and 2 are the main degradation enzymes of proteoglycan, and their activity is strongly inhibited by tissue inhibitor of metalloproteinase 3 (TIMP-3). Le Maitre CL et al. showed that the increased expression of Aggrecanase 1 in the nucleus pulposus cells of the intervertebral disc could lead to degeneration of the intervertebral disc.

Ismail et al. showed that ADAMTS-5 is a major aggrecanase in human chondrocytes and is involved in the regulation of ACAN degradation by IL-1. The TRAF-6/TAK-1/MKKK-4 signal axis is required for IL-1 to induce ACAN degradation, whereas NF-Κb is not. Among the three MAPKs (ERK, p38, and JNK), only JNK-2 showed a significant effect in ACAN degradation. Chondrocytes secrete aggrecanase, which is continuously endocytosed by LRP-1, keeping the extracellular level of aggrecanase low.

Germaschewski et al. have developed a new epitope immunoassay to specifically analyze the degradation products of ACAN, whether from MMP or aggrecanase. The researchers analyzed patients with knee osteoarthritis and healthy subjects and tested the pharmacodynamic effects of the humanized monoclonal antibody ADAMTS-5 as a potential disease modifying agent for OA, which can quantify the concentration of ARGS(the degradation of ACAN by ADAMTS-5 enzyme). The detection method is more sensitive, and the measurement of the new epitope of ARGS can be used as a prognostic or stratified marker.

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