CC chemokines and receptors in osteoarthritis: new insights and potential targets

Abstract

Osteoarthritis (OA) is a prevalent degenerative disease accompanied by the activation of innate and adaptive immune systems-associated inflammatory responses. Due to the local inflammation, the expression of various cytokines was altered in affected joints, including CC motif chemokine ligands (CCLs) and their receptors (CCRs). As essential members of chemokines, CCLs and CCRs played an important role in the pathogenesis and treatment of OA. The bindings between CCLs and CCRs on the chondrocyte membrane promoted chondrocyte apoptosis and the release of multiple matrix-degrading enzymes, which resulted in cartilage degradation. In addition, CCLs and CCRs had chemoattractant functions to attract various immune cells to osteoarthritic joints, further leading to the aggravation of local inflammation. Furthermore, in the nerve endings of joints, CCLs and CCRs, along with several cellular factors, contributed to pain hypersensitivity by releasing neurotransmitters in the spinal cord. Given this family’s diverse and complex functions, targeting the functional network of CCLs and CCRs is a promising strategy for the prognosis and treatment of OA in the future.

Osteoarthritis in the Elderly Population: Preclinical Evidence of Nutrigenomic Activities of Flavonoids

“…These aspects are of particular importance in the elderly and obese populations, which physiologically develop “inflammaging”, a low grade of systemic inflammation, which is a possible cause of the development and progression of OA. For these reasons, age and overweight represent the strongest risk factors for OA, since they lead to a reduction in the regenerative capacity of chondrocytes, as well as in the maintenance of cartilage homeostasis, where the accumulation of risk factors perturb this equilibrium [ 91 ]. Initially, chondrocytes were the only cell type considered in OA etiopathogenesis, and as cartilage is not vascularized, local or systemic inflammation was not taken into account.…”

“…Although many works highlighted how many phytochemicals have an anti-osteoarthritic activity, few molecules have been investigated in all aspects related to the disease. For example, since inflammation is able to alter DNA methylation of pro-inflammatory genes, increasing their expression in several biological systems [ 87 , 88 , 89 ], and considering the nutrigenomics effects of dietary compounds on DNA methylation even in pathologies with inflammatory etiologies [ 90 , 91 ], further nutrigenomic in vitro studies and in vivo preclinical investigations, with the support of in silico studies, will be of great help in the future use of the flavonoids as treatment or co-treatment of OA. The main limit to their use as anti-arthritic drugs (see Outstanding Issues) is due to the lack of specific studies on the real mechanisms of action on cartilage in patients with OA.…”

The role of monocyte/macrophage chemokines in pathogenesis of osteoarthritis: A review

“…Monocyte/macrophage chemokines transfer signals and activate downstream pathways through G protein-coupled receptor in the cell surface, regulating the structure and expression of adhesion molecule and cytoskeletal protein of target cells. These cytokines, as chemical attractants, modulate the chemotactic action on monocytes/macrophages by creating concentration gradients, thus playing an important role in hosting immune defence and tissue catabolic responses (Hughes & Nibbs, 2018;Stone et al, 2017;Wolpe & Cerami, 1989;Zhang et al, 2023). They are also involved in the development of many diseases, such as cancers (Korbecki et al, 2020), neuroinflammatory diseases (Gyoneva & Ransohoff, 2015), rheumatoid arthritis (Öckinger et al, 2010) and cardiovascular diseases (White et al, 2013;Zhang et al, 2022).…”

“…When monocyte/macrophage chemokines bind to G protein-coupled receptors on the surface of cell membranes, they induce the conversion between guanosine diphosphate and triphosphate on the Gα subunit, which subsequently activate the downstream pathway, including adenylate cyclase-cyclic adenosine monophosphate-protein kinase A pathway and phospholipase C-IP3-PKC signalling pathways (Gilchrist, 2020;Zhang et al, 2023), forming complex regulatory networks and leading to phenotypic changes through biochemical cascades, as shown in Table 2 .…”

Adipose-derived regenerative therapies for the treatment of knee osteoarthritis

“…Activation of NF-κB pathways by IL-1β has also been shown to increase the production of chemokines by chondrocytes, including chemokine (C-C motif) ligand (CCL)-2[ 30 ], which play an important role in osteoarthritis pathogenesis[ 31 ]. CCL-2 is considered a key factor in initiating and propagating chronic inflammation in osteoarthritis[ 32 - 34 ], and its deletion is considered chondroprotective. It is responsible for recruiting pro-inflammatory, M1, macrophages to the site of injury, and may act in an autocrine fashion leading to upregulated expression of CCL-2 itself, chondrocyte apoptosis, and greater MMP expression via the MAPK pathway[ 35 ], another principal pathway involved in osteoarthritis pathogenesis alongside NF-κB signaling[ 26 ].…”