Research progress of connexin 43 mediated gap junction communication regulating bone metabolism in glucocorticoid-induced osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) is a refractory orthopedic disease that commonly affects young and middle-aged individuals. Long-term and high-dose use of glucocorticoids (GCs) is one of the main causes. Currently, the pathological mechanism of GCs-induced ONFH remains unclear, which poses difficulties for clinical prevention and treatment. This article focuses on reviewing the roles of gap junctions (GJs) and connexin 43 (Cx43) in GCs-induced ONFH. Under normal circumstances, cells in bone tissue form a network structure through GJs to maintain bone metabolic balance. However, GCs can obstruct the normal connections and signal transmission between bone tissue cells, leading to bone metabolic imbalance and triggering ONFH. As a key component of GJs in bone tissue, Cx43 is of great significance in bone metabolism. It not only participates in the construction of the osteocyte network but also regulates osteocyte activity, osteoblast differentiation, and osteogenic activities. Meanwhile, in vascular endothelial cells, Cx43 plays an important role in angiogenesis and maintaining vascular homeostasis, and is closely related to the vascularization of bone tissue. In addition, Cx43 is associated with the release of prostaglandin E2 (PGE2). GCs can inhibit the activity of Cx43, reduce the release of PGE2, and disrupt the balance of bone metabolism. Studies have shown that measuring changes in the expression level of Cx43 is expected to become an early diagnostic biomarker for GCs-induced ONFH. Enhancing its expression through small - molecule drugs, biological agents, and gene therapy may be potential treatment approaches for ONFH. This article proposes the PI3K/Akt/GSK3β/β-catenin pathway and conducts research on the regulatory mechanism of Cx43-mediated GJ-based intercellular communication, aiming to provide new ideas for the treatment of ONFH and bone metabolism-related diseases.