Phosphatidylinositol-3-kinase/protein kinase B signaling dysregulation in steroid-induced osteonecrosis of the femoral head: A minireview of therapeutic implications

Abstract

Steroid-induced osteonecrosis of the femoral head (SIONFH) is a serious complication of glucocorticoid (GC) therapy and is characterized by progressive bone collapse, ischemia, and impaired bone regeneration. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway plays a pivotal role in maintaining bone homeostasis by regulating proliferation, differentiation, and survival of osteoblasts, osteoclasts, mesenchymal stem cells, and vascular endothelial cells. This minireview summarizes the mechanisms by which GCs disrupt PI3K/AKT signaling and the pathological consequences. The main results from the literature indicate that GCs suppress PI3K/AKT signaling in osteoblasts, leading to increased apoptosis and reduced bone formation. GCs also alter PI3K/ AKT-mediated signaling to promote osteoclast activity, shift bone marrow stromal cell differentiation toward adipogenesis, and induce endothelial dysfunction, all of which contribute to SIONFH pathogenesis. Consequently, targeting the PI3K/AKT pathway has emerged as a promising therapeutic strategy. Emerging interventions, including PI3K/AKT activators like insulin growth factor 1, stem cell therapies, and exosome-based treatments, have shown preclinical efficacy. In conclusion, the PI3K/AKT pathway is a central hub in SIONFH pathogenesis, and its modulation offers a promising avenue for developing novel targeted and personalized therapeutic approaches. Further investigation is essential to translate these preclinical findings into effective clinical treatments.

Keywords: Femoral head necrosis; Phosphatidylinositol-3-kinase/protein kinase B signaling pathway; Glucocorticoids; Angiogenesis; Apoptosis; Molecular targeted therapy; Cell differentiation

Core Tip: Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating disorder associated with prolonged glucocorticoid therapy. The phosphatidylinositol-3-kinase/protein kinase B signaling pathway plays a critical role in regulating the survival, differentiation, and angiogenesis of bone cells. This mini-review highlighted how glucocorticoid-induced dysregulation of the phosphatidylinositol-3-kinase/protein kinase B pathway in osteoblasts, osteoclasts, mesenchymal stem cells, and endothelial cells contributed to the pathogenesis of SIONFH. We reviewed emerging therapeutic strategies targeting this pathway and provided new insights into potential interventions for early-stage SIONFH.