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Metabolic Approaches to the Treatment of Back Pain
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Carrie Diulus, Patrick Hanaway
Spine providers have long been aware of genetic predisposition to degenerative changes in the spine and resultant axial back pain. Family history is an important part of the clinical evaluation for patients with back pain. Recent research has identified SNPs and other genetic factors associated with spinal degeneration, including: rs1337185 and rs1676486 in COL1A1 and rs162509 in ADAMTS5. COL1A1 is a structural gene expressed in the intervertebral disc and encodes the alpha-1 chain of type XI collagen. ADAMTS-4 and ADAMTS-5 are degradative genes in the metalloprotease family. COL1A1 SP1 (a collagen I SNP), COL9a3 Trp2 and Trp3 (a collagen IX SNP), and VDR TaqI (a vitamin D receptor SNP) correlated with lumbar disc degeneration that is proportional to the number of mutations [7–14]. The science around the genetic factors is in its infancy – family history is an important consideration for risk. Genomic SNPs may highlight predisposition to pain, as well as response to standard therapeutic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids.
Advances in Osteoarthritis of the Hip
Published in K. Mohan Iyer, Hip Joint in Adults: Advances and Developments, 2018
Pratham Surya, Sriram Srinivasan, Dipen K. Menon
There are a number of potential targets that can be manipulated to alter the course of OA. Research is ongoing to develop effective drugs in this area. Calcitonin is in trial clinically as it has shown remarkable effects on bone remodelling. Vitamin D gets depleted in OA, and vitamin D replacement can benefit patients with OA. Some protease enzymes deplete certain enzymes and can have an adverse effect on articular cartilage. Inhibition of such proteases can be the potential target for treatment of OA. One such enzyme inhibitor, ADAMTS5, is being investigated [21].
Articular Cartilage Pathology and Therapies
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
How, then, does inflammation wreak such havoc on this tissue? As the disease progresses, the thickening and increasingly hypervascular synovium secretes MMPs and aggrecanases. The cleavage of aggrecan and the subsequent degradation of compressive properties are mediated by these aggrecanases. Aggrecanases belong to the A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) family, which includes ADAMTS4 and 5 (aggrecanase 1 and 2, respectively). IL-1 and TNF-α modulate the expression of ADAMTS4 to induce catabolism (Tortorella et al. 2001). However, ADAMTS5 is constitutively expressed (McCulloch et al. 2009); it must be remembered, though, given the shorter half-life of aggrecan, that both aggrecanases have natural functions in tissue remodeling in healthy tissue, versus their function in the disease state.
Ginkgetin Alleviates Intervertebral Disc Degeneration by Inhibiting Apoptosis, Inflammation, and Disturbance of Extracellular Matrix Synthesis and Catabolism via Inactivation of NLRP3 Inflammasome
Published in Immunological Investigations, 2023
Baoshan Hu, Shan Lin, Shengrong Lin, Gang Rui
The synthesis and catabolism of ECM are another significant pathogenesis involved in the progression of IDD, in which ECM degradation always occurs, thereby resulting in the dysregulation of the synthesis and catabolism of the ECM (Tao et al. 2016). ECM that mainly comprises of proteoglycans and collagen is highly organized in IVD, which is momentous to maintain the proper spine mechanics (Colombini et al. 2008). Collagen II and aggrecan, the primary ingredients of NP ECM, serve crucial roles in maintaining the osmotic pressure and elasticity of the disc (Xu et al. 2019). ADAMTS5 and MMP13 are proteolytic enzymes that play central roles in controlling the ECM catabolism (Wang et al. 2015). Here, the relative mRNA and protein expressions of ADAMTS5 and MMP13 were enhanced, and these of Collagen II and Aggrecan were downregulated in IL-1β-induced NPCs, which indicated an imbalance in the ECM synthesis and catabolism in IL-1β-induced NPCs, in line with the results shown in a recent report (Bai et al. 2022). Administration of GK reversed the IL-1β-induced the mRNA and protein expressions of ADAMTS5, MMP13, Collagen II and Aggrecan of NPCs, which demonstrated that GK attenuated the ECM degradation in IL-1β-induced NPCs. More importantly, GK also inverted the translational expressions of ADAMTS5, MMP13, Collagen II and Aggrecan of NPCs in IDD rats. Wei et al. (2021) revealed that GK dampens ECM deposition in high glucose-elicited mesangial cell. Therefore, all the results elucidated that GK restrained the ECM degradation in IDD.
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.
Are serum levels of ADAMTS5, TAS and TOS at 24–28 gestational weeks associated with adverse perinatal outcomes in gestational diabetic women?
Published in Journal of Obstetrics and Gynaecology, 2020
Sibel Ozler, Efser Oztas, Basak Gumus Guler, Ozcan Erel, Ali Turhan Caglar, Merve Ergin, Dilek Uygur, Nuri Danisman
ECM remodeling is controlled by specific proteases and various members of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes are known to function in the cleavage and degradation of ECM components (Gabbay-Benziv and Baschat 2015). Some ADAMTS subtypes such as ADAMTS5 and ADAMTS11 were shown to play important roles in implantation and placentation processes by the studies of term human placenta and uterine tissues (Abbaszade et al. 1999; Vazquez et al. 1999; Calderon et al. 2007). ADAMTS5 is also named as aggrecanase–2 (chondroitin sulfate proteoglycanase) (Hurskainen et al. 1999). ADAMTS5 causes the functional and structural changes in ECM by cleavage of the proteoglycans such as aggrecan, versican and brevican (Stanton et al. 2005; McCulloch et al. 2009). Kumar et al. (2012) have shown that anti-angiogenetic effect of ADAMTS5 by inhibiting angiogenetic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and platelet-derived endothelial growth factor (PDECGF) (Blumer et al. 2013). Daniel et al. demonstrated the blockage of glucose uptake by ADAMTS5 in the cultures of adipose tissue-derived stromal cells (ADSC) and epiphyseal chondrocytes of knock-out mice; resulting in inhibition of aggrecan and versican synthesis and degradation of the intracellular matrix (Daniel et al. 2015).