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The ACAN (aggrecan)gene is located at 15q25-q26.2, which consists of 19 exons ranging in size from 77 to 4224 bp. ACAN is an important component of the extracellular matrix of the intervertebral disc nucleus, accounting for approximately 70% of the dry weight of the nucleus pulposus. Studies have shown that collectin proteoglycans are central hyaluronic acid (HA) filaments linked to ACAN and connexin (LP). The core protein domain of ACAN is a G1, G2, G3 globular region; IGD, intersphere domain; KS, a keratan sulfate-rich domain; CS1 and CS2, a chondroitin sulfate-rich domain.
In 1997, Doege et al. found that there is a variable number of tandem repeat (VNTR) polymorphisms on the 12th exon of the human ACAN gene, which means that the number of repeats of the gene fragment is different, leading to different lengths of the fragment. The ACAN gene polymorphism is actually a repeat polymorphism. This polymorphism has not been found in other species so far. The number of repeats may determine the length of the domain in the core protein, which in turn determines the number of chondroitin sulfate chains attached to it, confirming the functional characteristics of proteoglycans at the genetic and molecular levels.
For ideal tissue function, ACAN concentration, charge and size must be as large as possible. Thus, the optimal ACAN molecule achieves the largest substitution, the longest and most sulfated GAG chain through the GAG chain and forms the largest aggregate with HA. Proteoglycan aggregates are thought to be encapsulated by collagen fibers. In the relaxed state, when the anionic chondroitin sulfate and the keratan sulfate chain inhale water into the tissue, the aggregate swells until equilibrium is reached, wherein the swelling is balanced by the tension in the collagen fibers. Under compression, water is displaced and the chondroitin sulfate and keratan sulfate chains are closer, thus increasing their swelling potential and balancing the applied load. When the original balance is restored, the increased expansion potential is dissipated by the time the load is removed.
Figure 1. The function of ACAN in articular cartilage. (Roughley P J, et al. 2014)
ACAN and Degeneration of The Intervertebral Disc
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.
ACAN and Osteoarthritis
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.