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Basic Science of Osteoarthritis
Published in Manoj Ramachandran, Tom Nunn, Basic Orthopaedic Sciences, 2018
Loss of the large aggregating proteoglycan, aggrecan, is a consistent and early biochemical finding. There is a rapid loss of proteoglycan that progresses with disease severity. This is due to a combination of leaching from the damaged collagen network and enzymatic breakdown. There is a compensatory increase in proteoglycan synthesis by chondrocytes, particularly in early OA. This leads to changes in glycosaminoglycan (GAG) composition: the ratio of chondroitin sulphate to keratan sulphate (KS) is increased, and there is relatively more choindroitin-4 sulphate than chrondroitin-6 sulphate. As OA progresses, the proteoglycan chain lengths are shorter. Aggregation is reduced due to proteolytic activity at the hyaluronic acid binding region of the core protein.
Structure and Function of Cartilage
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Aggrecan exists as a large, highly glycosylated proteoglycan with long, linear GAG chains of chondroitin sulfate and keratan sulfate molecules radiating from a central ∼230 kDa protein core, resulting in a bottle brush structure (Table 1.2). Aggrecan is posttranslationally modified by glycosylation in the late endoplasmic reticulum (specifically an initial xylosylation); the molecular mass of a single proteoglycan can reach more than 2 MDa (Watanabe et al. 1998). The protein core contains several distinct globular domains (G1, G2, and G3), an interglobular domain, and two extended domains where GAGs attach, the keratan sulfate (KS) and chondroitin sulfate (CS) domains (Figure 1.24). The globular domains are involved in aggregate formation, while the interglobular domain contains sites available for proteolytic cleavage and is likely involved in the turnover of aggrecan. The KS domain is absent in rodents (Kiani et al. 2002). The CS domain represents the largest domain in aggrecan and is encoded by a single exon (exon 12) representing a 120-repeat serine-glycine sequence. The carboxyl (COO−) and sulfate SO3− groups present on these attached GAGs produce a strong negative charge that in turn gives cartilage extracellular matrix a net negative charge known as a “fixed charge density,” with a charge spacing of 1–2 nm per GAG (Maroudas et al. 1969).
Aspartic Acid Racemization and Aging in Cartilaginous Tissue
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Sarit Sara Sivan, Alice Maroudas, Ellen Wachtel
Turnover is a decreasing function of age and is consistently higher for degenerate IVD as compared to normal. The mean turnover rate for aggrecan from normal tissue is 0.138 year-1 and the mean half-life, 5.2 years. Calculating aggrecan half-life (defined by Equation 4) for different age groups gives Fig. 3A.
CircSCAPER knockdown attenuates IL-1β-induced chondrocyte injury by miR-127-5p/TLR4 axis in osteoarthritis
Published in Autoimmunity, 2022
Yuchang Zhang, Ping Zhao, Sen Li, Xiangqian Mu, Huaqi Wang
Chondrocytes are the main cell population of cartilage and engaged in the synthesis and degradation of ECM in cartilage [27]. Chondrocyte apoptosis has been revealed to be closely related to articular cartilage destruction and ECM degradation during the progression of OA [28]. Aggrecan is the core proteins of the ECM in articular cartilage [29]. MMP-13, an ECM-degrading enzyme, regulates tissue modelling and repair, overexpression of which can lead to pathological mutations through extreme ECM degradation [30]. During the progression of OA, tissues throughout the OA joint are involved in the inflammatory process [25]. IL-1β is a significant pro-inflammatory cytokine, which can induce chondrocyte apoptosis, cause ECM degradation and joint inflammation, thus making for the progression of OA [4, 31]. Recently, circSCAPER reversed IL-1β-evoked inhibition of growth and ECM degradation in chondrocytes, indicating the involvement of circSCAPER in OA process. Consistent with these findings, our study also found that circSCAPER was highly expressed in the OA cartilages and IL-1β-induced chondrocytes, and knockdown of circSCAPER suppressed the apoptosis and ECM degradation in chondrocytes. In addition, we also confirmed that the release of proinflammatory cytokines and oxidative damage caused by IL-1β in chondrocytes were attenuated by circSCAPER silencing. Thus, circSCAPER siRNA may be a new molecule that can be used to prevent OA progression.
Knockdown of circ-PRKCH alleviates IL-1β-treated chondrocyte cell phenotypic changes through modulating miR-502-5p/ADAMTS5 axis
Published in Autoimmunity, 2022
Zhongxing Liu, Jian Cao, Limin Zhang, Jinlong Li, Tinghan Yan, Peng Zhou, Sidi Zhang
Aggrecan is the main component of ECM and an indicator of OA progression [39]. ADAMTS5, an aggrecanases, which participates in the pathogenesis of OA by degrading Aggrecan [40]. Elsadek et al. demonstrated that the serum level of ADAMTS5 in OA rats is a promising indicator for the diagnosis and prognosis of OA [41]. In addition, ADAMTS5 silence contributed to the expression of Aggrecan to accelerate chondrogenic differentiation in OA [42]. Lu et al. suggested that hsa-miR-15a ameliorated OA progression via negatively regulating ADAMTS5 [43]. In this research, we affirmed that ADAMTS5 was a target of miR-502-5p, and it was up-regulated in OA cartilages and IL-1β-treated chondrocytes. Besides, ADAMTS5 was reversely regulated by miR-502-5p. Rescue experiments revealed that miR-502-5p exerted a protective effect in IL-1β-treated chondrocytes by binding to ADAMTS5. Also, circ-PRKCH was confirmed to regulate ADAMTS5 expression via sponging miR-502-5p.
Platelet-rich plasma treatment alleviates osteoarthritis-related pain, inflammation, and apoptosis by upregulating the expression levels of microRNA-375 and microRNA-337
Published in Immunopharmacology and Immunotoxicology, 2022
Xuegang Sun, Lidong Mi, Guangyu Du, Chuanxiu Sun, Shengwei He
Abnormally expressed inflammatory factors, such as TNF-α and IL-1β, are always observed in OA [49,50]. A study has reported that PRP decreased the expression of these inflammatory factors (TNF-α and IL-1β) as well as the degree of cartilage degeneration in OA rabbits [51]. It is believed that IL-1β induces the regression of the extracellular matrix as well as the programmed death of chondrocytes and tendocytes. Moreover, it induces the production of multiple proteolytic enzymes but inhibits the production of extracellular matrix proteins, including aggrecan and collagen. In contrast, chondrocyte studies have shown that PRP inhibits matrix loss, which was also evident in the current study. Our in vitro study used IL-1β to stimulate chondrocytes to mimic OA at the cell level. The increase in apoptosis and inflammation observed suggested that an OA cell model was successfully established. Furthermore, PRP administration ameliorated the effects of IL-1β on inflammation and the associated Wnt1/β-catenin pathway. Further, chondrocyte apoptosis was ameliorated after PRP incubation. Our data also indicate that miR-337 inhibition, but not that of miR-375, increases the production of inflammatory factors in vivo and in vitro.