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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
Though chondrocytes have been categorized as all belonging to the same phenotype, differences exist in the genetic, synthetic, and mechanical characteristics of cells with respect to their zone of origin in the tissue (Aydelotte and Kuettner 1988; Darling et al. 2004, 2006; Darling and Athanasiou 2005). For instance, superficial zone chondrocytes express the protein proteoglycan 4 (PRG4), also termed lubricin or superficial zone protein (SZP), while middle zone chondrocytes express cartilage intermediate-layer protein (CILP). Superficial zone chondrocytes were also found to attach to tissue culture plastic slower than those from the deeper zones (Siczkowski and Watt 1990). Deep zone cells display a higher level of vimentin (Durrant et al. 1999), which has been hypothesized to resist compression of the cell (Ghadially 1983; Ralphs et al. 1992). Keratan sulfate synthesis has also been observed to gradually increase through cartilage depth (Zanetti et al. 1985; Aydelotte et al. 1988; Aydelotte and Kuettner 1988; Archer et al. 1990; Siczkowski and Watt 1990). The characteristic gene and protein expressions of chondrocytes are closely associated with the matrix constituents of articular cartilage.
Emerging therapeutic targets for osteoarthritis
Published in Expert Opinion on Therapeutic Targets, 2023
The Wnt/β-catenin pathway has long been understood to be a key regulator of OA pathogenesis due to its importance in skeletal development, controlling the differentiation of chondrocytes, osteoblasts, and osteoclasts and ensuring the development of synovial joints [61]. As such, therapeutic interventions need to be careful in modulating this pathway. Indeed, both upregulation and downregulation of the Wnt/β-catenin signaling pathway may amplify OA [62,63]. Recent work by Lietman and colleagues [64] injected mice with XAV-939 (small-molecule Wnt/β-catenin inhibitor) following DMM surgery and demonstrated an attenuation of cartilage degeneration and synovitis. This is accompanied by an increase in type II collagen and proteoglycan 4 (Prg4/lubricin), leading to cartilage protection, and a decrease in synovial fibroblast proliferation, resulting in reduced type I collagen synthesis. Other work has noted that overexpression of Wnt signaling increases MMP-1 and -9 production, demonstrating another mechanism for which the Wnt pathway may increase cartilage degeneration [65].
Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies
Published in OncoImmunology, 2022
Rebecca Adams, Gabriel Osborn, Bipashna Mukhia, Roman Laddach, Zena Willsmore, Alicia Chenoweth, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Linda Barber, Sophia Tsoka, Victoria Sanz-Moreno, Katie E Lacy, Sophia N Karagiannis
Chondroitin sulfate proteoglycan 4 (CSPG4) is a cancer antigen which may be more selective for cancer cells. CSPG4 is expressed in 70% of the melanomas with a low and restricted expression profile in healthy tissue.133 Monoclonal antibodies designed against this target which can engage the FcRs on immune cells, including monocytes and macrophages, are under development in preclinical models. An anti-CSPG4 IgG1 monoclonal antibody has been reported to increase macrophage recruitment in a fully humanized mouse model of melanoma,118 and repeated administration of an anti-CSPG4 IgE monoclonal antibody therapy is well tolerated in immunocompetent animal models.133 The exact effect of anti-CSPG4 mAbs on macrophages remains unknown but warrants exploration, since polarizing TAMs and enhancing their antitumor properties may be a potential mechanism by which anti-CSPG4 can exert therapeutic effects.
Chimeric antigen receptor T-cell therapy for melanoma
Published in Expert Review of Clinical Immunology, 2021
Azadehsadat Razavi, Mahsa Keshavarz-Fathi, John Pawelek, Nima Rezaei
It should also be mentioned that choosing the right, most stable target antigen for CAR T cells has always been an important issue for producing a durable response [155–157]. Overexpressed tumor antigens represented on melanoma surface are considered as appropriate antigens for engineered CAR T cells. The upregulation of L1-CAM (CD171) on melanoma makes it a potential therapeutic target [158]. One of the heavily glycosylated transmembrane proteins, chondroitin sulfate proteoglycan 4 (CSPG4), whose overexpression has been reported in melanoma, is a potential target for CAR-engineered T cell immunotherapy [159]. This molecule acts in fundamental activities of tumor like migration, invasion, angiogenesis, and metastasis [160]. CSPG4-CAR-T cells have already been used for targeting CSPG4 expressed on cutaneous melanoma cells [159,161] so the hypothesis that NG2/CSPG4 may be a specific target for CAR T cells for MM patients has been strengthened. Researchers have identified other molecules such as ganglioside GD2, ganglioside GD3, Glypican-3 (GPC3), HER2, the human endogenous retrovirus (HERV-K) envelope (env) protein, podoplanin (PDPN), and tissue factor (TF), which are proper for designing targeted CAR T cells for patients with melanoma [141,162–167].