Analysis of the function and therapeutic strategy of connexin 43 from its subcellular localization.

Connexins (Cxs) are a family of transmembrane proteins located in the plasma membrane of human cells, among which connexin 43 (Cx43) is abundantly expressed in various types of human cells. Cx43, encoded by the gap junction protein alpha 1 (GJA1) gene, assembles into a hexameric structure in the Golgi apparatus and translocates to the plasma membrane to form hemichannels (Hcs), which pair with those of the cells in contact with each other and form gap junction intercellular communication (GJIC). The role of Cx43 as a connexin localized at the plasma membrane to perform channel functions is well recognized in previous studies, but recent studies have found that it can also be localized in the nucleus, mitochondria, or present in extracellular vesicles (EVs) and tunneling nanotubes (TNTs). Cx43 in the nucleus is involved in gene transcription regulation, cytoskeleton formation, cell migration and adhesion. Cx43 in mitochondria is involved in mitochondrial respiration-related functions, and Cx43 in extracellular vesicles and tunneling nanotubes is involved in distant cellular information exchange. It is because of the diverse distribution of subcellular localization of Cx43 that it is possible to explore the corresponding functions by analyzing its localization. In this review, we summarize the important roles of Cx43 in disease development from the perspective of subcellular localization, and provide new ideas for Cx43 as a therapeutic target and the search for related pathological mechanisms.

The role of AGEs in pathogenesis of cartilage destruction in osteoarthritis.

Osteoarthritis (OA) is a degenerative disease resulting from progressive joint destruction caused by many factors. Its pathogenesis is complex and has not been elucidated to date. Advanced glycation end products (AGEs) are a series of irreversible and stable macromolecular complexes formed by reducing sugar with protein, lipid, and nucleic acid through a non-enzymatic glycosylation reaction (Maillard reaction). They are an important indicator of the degree of ageing. Currently, it is considered that AGEs accumulation in vivo is a molecular basis of age-induced OA, and AGEs production and accumulation in vivo is one of the important reasons for the induction and acceleration of the pathological changes of OA. In recent years, it has been found that AGEs are involved in a variety of pathological processes of OA, including extracellular matrix degradation, chondrocyte apoptosis, and autophagy. Clearly, AGEs play an important role in regulating the expression of OA-related genes and maintaining the chondrocyte phenotype and the stability of the intra-articular environment. This article reviews the latest research results of AGEs in a variety of pathological processes of OA, to provide a new direction for the study of OA pathogenesis and a new target for prevention and treatment. Cite this article: Bone Joint Res 2022;11(5):292-300.

The Function of PPARγ/AMPK/SIRT-1 Pathway in Inflammatory Response of Human Articular Chondrocytes Stimulated by Advanced Glycation End Products.

Accumulation of advanced glycation end products (AGEs) in the articular cartilage is a major risk factor for osteoarthritis (OA). To determine the mechanistic basis of AGE action in OA, we treated human articular chondrocytes with AGEs, and found that they not only up-regulated the pro-inflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, but also inhibited AMP-activated protein kinase (AMPK) phosphorylation and decreased sirtuin 1 (SIRT-1) levels in a concentration- and time-dependent manner. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist restored the inhibited AMPK and SIRT-1 by AGEs. Pre-treatment of the cells with the agonists or antagonists of AMPK and SIRT-1 respectively abolished and augmented the inflammatory state induced by AGEs. Furthermore, AMPK agonist also restored the levels of SIRT-1 in the AGE-stimulated chondrocytes. Our findings indicate AGEs induce an inflammatory response in human articular chondrocytes via the PPARγ/AMPK/SIRT-1 pathway, which is therefore a potential target in OA therapy.