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.

Key Words: 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.

INTRODUCTION

Glucocorticoids (GCs) are anti-inflammatory and immunomodulatory agents widely used in the treatment of rheumatic diseases, autoimmune disorders, and immunosuppression during organ transplantation[1]. However, long-term or high-dose GC therapy often results in steroid-induced osteonecrosis of the femoral head (SIONFH), which is a severe and debilitating complication that primarily affects middle-aged and young adults. SIONFH is initially characterized by subtle clinical symptoms that progress to the collapse of the femoral head[2]. In advanced stages, it frequently requires total hip arthroplasty and significantly reduces the patient’s quality of life. SIONFH accounts for approximately 30%-40% of non-traumatic osteonecrosis cases[3]. Its precise pathogenesis remains unclear, and early intervention and targeted treatment options are limited.

The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway regulates critical cellular processes such as proliferation, differentiation, apoptosis, and metabolic homeostasis[4]. Activation of this pathway occurs through extracellular signals mediated by receptor tyrosine kinases and G-protein coupled receptors, triggering a phosphorylation cascade that converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and activates AKT for downstream signaling[5]. In the skeletal system, the PI3K/AKT pathway maintains bone homeostasis by responding to growth factors and hormonal signals. It precisely regulates the proliferation, differentiation, and survival of osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells (BMSCs) and participates in bone matrix synthesis and remodeling to maintain bone tissue balance[6].

Current treatments for SIONFH include conservative and surgical approaches, but they have limited effectiveness[7], especially for younger patients concerned with long-term complications of total hip arthroplasty. Therefore, identifying new pathophysiological targets and developing strategies to delay or prevent early-stage SIONFH is a critical clinical priority. Studies have indicated that the PI3K/AKT pathway plays a central role in the pathogenesis of SIONFH[1]. GCs disrupt this pathway through various mechanisms, causing increased osteocyte apoptosis, impaired angiogenesis, and abnormal lipid metabolism, all of which contribute to disease progression[8]. This mini-review summarizes the recent studies on the dysregulation of the PI3K/AKT pathway in different bone cell types in SIONFH, elucidating the intercellular communication and molecular crosstalk mechanisms and exploring the therapeutic potential of targeting this pathway[9]. The review highlighted new therapeutic strategies and provided new theoretical frameworks and clinical insights for the prevention and treatment of SIONFH.

METHODOLOGY

This study is a narrative minireview. A comprehensive literature search was conducted in the PubMed/MEDLINE, EMBASE, and Web of Science databases to identify articles published from inception up to December 2024. The search terms included various combinations of the following: “steroid-induced osteonecrosis”, “glucocorticoids”, “femoral head necrosis”, “PI3K/AKT signaling pathway”, “apoptosis”, “angiogenesis”, “cell differentiation”, “osteoblast”, “osteoclast”, “mesenchymal stem cells”, and “molecular targeted therapy”. The search focused primarily on English-language publications, but relevant articles in other languages were also considered. Both preclinical studies (including those involving in vitro cell culture and in vivo animal models) and clinical research were included to provide a comprehensive overview of the topic. The literature search was performed by Wang YN and Pang CX, with the final list of included studies reviewed and approved by Jiang HJ.

PHYSIOLOGICAL ROLES OF PI3K/AKT SIGNALING IN BONE HOMEOSTASIS

The PI3K/AKT signaling pathway is a central regulator of skeletal homeostasis. It coordinates the biological functions of various bone cell types, including osteoblasts, osteoclasts, and BMSCs, and maintains bone tissue equilibrium. Under physiological conditions, the PI3K/AKT pathway acts downstream of multiple growth factors (e.g., insulin-like growth factor 1) and hormonal signals[10]. In osteoblasts, the PI3K/AKT pathway enhances protein synthesis by activating the mammalian target of rapamycin (mTOR) pathway and suppresses autophagy[11]. It also inhibits glycogen synthase kinase 3 β activity to stabilize β-catenin. Together, these actions promote osteoblast proliferation and differentiation. The pathway also activates transcription factors such as Runx2 and Osterix, which upregulate alkaline phosphatase and bone matrix proteins, including type I collagen, osteocalcin, important for bone matrix synthesis and mineralization. Additionally, the PI3K/AKT pathway promotes osteoblast survival[12]. It inhibits proapoptotic molecules such as Bax and caspase-3 and upregulates anti-apoptotic proteins like B-cell lymphocyte/Leukemia 2, which prevents premature osteoblast apoptosis. PI3K/AKT signaling regulates osteoclast formation, activation, and bone resorption activity. Its effects vary with different cellular environments, and it modulates cell survival, differentiation, and cytoskeletal organization. In BMSCs, the PI3K/AKT pathway acts as a fate determinant. It promotes osteogenic differentiation by activating Runx2 and Osterix, while suppressing the adipogenic transcription factor proliferator-activated receptor gamma[13]. This regulation prevents excessive adipogenesis and maintains the balance between osteogenesis and adipogenesis.

DYSREGULATION OF PI3K/AKT SIGNALING BY GCs IN SIONFH PATHOGENESIS

GC-mediated inhibition of PI3K/AKT signaling in osteoblasts and pathological consequences

GCs are key pathogenic factors that induce osteoblast dysfunction and apoptosis through multiple mechanisms, including inhibition of PI3K/AKT signaling. First, GCs directly inhibit PI3K activity, which decreases PIP3 production[14]. When PI3K activity is inhibited, then AKT phosphorylation and downstream signaling are decreased. Second, GCs increase the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene and negative regulator of the PI3K/AKT pathway. PTEN dephosphorylates PIP3 to phosphatidylinositol 4,5-bisphosphate, further reducing AKT activation. This inhibition of the PI3K/AKT pathway directly affects several key downstream effectors[15] (e.g., inhibition of mTOR signaling results in decreased protein synthesis and dysregulated autophagy). These changes impair osteoblast proliferation.

Reduced AKT phosphorylation also activates glycogen synthase kinase 3 β, leading to increased β-catenin degradation and ultimately suppressing osteoblast differentiation. Additionally, GCs worsen osteoblast dysfunction by regulating transcription factor forkhead box O1 (FOXO1), a transcription factor that is an important downstream target of the PI3K/AKT pathway. Lower AKT activity reduces FOXO1 phosphorylation, leading to its accumulation in the nucleus and increasing its function as a transcriptional repressor. This leads to inhibition of osteoblast proliferation and differentiation and induces apoptosis[16]. Apoptosis is marked by increased levels of proapoptotic proteins Bax and cleaved caspase-3 and decreased anti-apoptotic protein B-cell lymphocyte/Leukemia 2. In summary, GCs inhibit the osteoblastic PI3K/AKT pathway through several mechanisms, leading to reduced osteoblast numbers and impaired function. These mechanisms contribute to inadequate bone formation and play a major role in the bone loss seen in SIONFH.

Complex effects of GCs on PI3K/AKT signaling in osteoclasts and their role in promoting bone resorption

The mechanisms and overall effects of GCs on the PI3K/AKT signaling pathway in osteoclasts are controversial. GCs can activate the PI3K/AKT pathway, promoting osteoclast formation and activity and enhancing bone resorption. GCs can also indirectly promote osteoclast differentiation and activation by altering the balance of the receptor activator of NF-kappaB ligand-osteoprotegerin system. In contrast, microRNAs (miRNAs), such as miR-21, have been identified as mediators of GC-induced regulation of osteoclasts[17]. miRNAs modulate the PI3K/AKT pathway by targeting molecules such as PTEN, thereby influencing osteoclast differentiation and function. Overall, clinical observations of increased bone resorption in patients with SIONFH suggest that GCs enhance (directly or indirectly) osteoclastic bone remodeling through unknown mechanisms, which exacerbate bone loss.

GC-induced disruption of BMSC differentiation balance and promotion of adipogenesis

The lineage commitment of BMSCs is essential for bone homeostasis. However, GCs disrupt this balance by promoting adipogenic differentiation at the expense of osteogenic differentiation[18], which is closely linked to dysregulation of the PI3K/AKT signaling pathway. Under physiological conditions, the PI3K/AKT pathway promotes osteogenic differentiation of BMSCs and suppresses adipogenesis. However, GC administration disrupts this equilibrium by directly inhibiting PI3K/AKT signaling in BMSCs, thereby reducing their osteogenic potential. This inhibition is partially mediated by the modulation of key pathway regulators, including PTEN and FOXO1. GCs also strongly activate the adipogenic transcription factor proliferator-activated receptor gamma, which markedly induces BMSC adipogenesis. Increased adipogenic differentiation reduces the pool of osteoprogenitor cells and increases the number and size of bone marrow adipocytes, leading to compression of intramedullary blood vessels and increased bone marrow pressure. All together, these alterations exacerbate ischemia in bone tissue and accelerate the progression of SIONFH[19].

GC-induced impairment of PI3K/AKT signaling in vascular endothelial cells and microcirculatory dysfunction

An adequate blood supply is essential for bone survival and function. The integrity of vascular endothelial cells is fundamental for maintaining normal tissue perfusion. The PI3K/AKT signaling pathway regulates endothelial cell proliferation, migration, and angiogenesis. However, GCs directly impair vascular endothelial cell function by suppressing the PI3K/AKT pathway. The expression and secretion of key angiogenic factors, such as vascular endothelial growth factor, are observed after this inhibition. As a result, both neovascularization and the maintenance of existing blood vessels are impaired. Consequently, vascular injury and impaired angiogenesis reduce blood flow in the femoral head, leading to microcirculatory dysfunction[20]. The hypoxic and ischemic conditions in bone tissue are exacerbated, ultimately promoting the onset and progression of SIONFH. The integrated mechanism is illustrated in Figure 1.

Figure 1 Mechanistic illustration of glucocorticoid disruption of phosphatidylinositol-3-kinase/protein kinase B signaling in steroid-induced osteonecrosis of the femoral head. Glucocorticoids (GCs) disrupt phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling in multiple bone-related cell types, contributing to steroid-induced osteonecrosis of the femoral head. In osteoblasts, GCs upregulate phosphatase and tensin homolog and forkhead box O1, reducing proliferation and matrix synthesis while increasing apoptosis. In osteoclasts, GCs enhance PI3K/AKT activity, promoting osteoclastogenesis and bone resorption. In bone marrow mesenchymal stem cells, GCs suppress PI3K/AKT and activate proliferator-activated receptor gamma, driving adipogenesis and increasing bone marrow pressure. In endothelial cells, GCs inhibit PI3K/AKT signaling and vascular endothelial growth factor secretion, impairing angiogenesis. These combined effects contribute to ischemia, bone collapse, and osteocyte death, which are hallmarks of steroid-induced osteonecrosis of the femoral head. GC: Glucocorticoid; PI3K/AKT: Phosphatidylinositol-3-kinase/protein kinase B; PTEN: Phosphatase and tensin homolog; FOXO1: Forkhead box O1; BMSC: Bone marrow mesenchymal stem cell; PPARγ: Proliferator-activated receptor gamma; SIONFH: Steroid-induced osteonecrosis of the femoral head; VEGF: Vascular endothelial growth factor.

THERAPEUTIC POTENTIAL OF PI3K/AKT PATHWAY TARGETING

Potential link between current therapeutic strategies for SIONFH and the PI3K/AKT signaling pathway

Current treatments for SIONFH may interact with the PI3K/AKT signaling pathway. Statins (e.g., pravastatin) are primarily used as lipid-lowering agents but have been shown to protect BMSCs by activating the PI3K/AKT pathway[21]. The activation enhances protective autophagy and may provide therapeutic benefits for patients with SIONFH. However, large-scale, high-quality randomized controlled trials are required to confirm these findings[22]. The role of anti-resorptive agents that are commonly used in osteoporosis management (e.g., bisphosphonates) is unknown in SIONFH. The specific interactions of anti-resorptive agents with the PI3K/AKT pathway are also unclear. In vitro studies suggest that bisphosphonates may modulate the PI3K/AKT pathway to inhibit osteoclast activity. However, concerns about their potential adverse effects on osteoblasts and the lack of robust clinical evidence supporting their safety and efficacy in SIONFH still remain. Future studies are needed to clarify the role of bisphosphonates for the treatment of SIONFH. Anticoagulants and vasodilators, which mainly improve local microcirculation, currently do not have direct associations with the PI3K/AKT pathway[23].

Novel therapeutic approaches targeting the PI3K/AKT signaling pathway

Because GCs markedly suppress the PI3K/AKT pathway, developing specific agonists or activators to restore pathway function is a promising therapeutic strategy. Insulin-like growth factor-1, a strong activator of the PI3K/AKT pathway, has shown preclinical efficacy in promoting fracture healing and preventing GC-induced osteoblast apoptosis[16]. mTOR is a critical downstream effector of the PI3K/AKT pathway and plays a regulatory role in bone repair. However, its specific application in SIONFH requires further study to assess therapeutic efficacy and safety. Notably, mTOR activators must be carefully selected and their mechanisms clearly defined. Cell-based therapies, particularly MSC transplantation, may provide novel therapeutic opportunities for SIONFH. MSCs have multilineage differentiation potential and secrete bioactive factors through paracrine signaling that can activate the PI3K/AKT pathway in host cells such as osteoblasts and endothelial cells[24]. This activation promotes bone regeneration and angiogenesis. The therapeutic efficacy of MSCs depends on both paracrine signaling and direct osteogenic differentiation that may be influenced by the status of the PI3K/AKT pathway. However, there are several challenges for introducing MSCs into the clinic, including optimization of cell sourcing, dosing, delivery methods, and post-transplant cell survival. Although a meta-analysis indicated that MSC transplantation improves clinical outcomes and imaging findings in patients with SIONFH, developing standardized protocols remains a priority for future research[25].

Exosomes are important mediators of intercellular communication that carry bioactive molecules such as proteins, messenger RNA, and miRNAs. MSC-derived exosomes modulate pathways such as PI3K/AKT by transferring their contents to target cells, thereby facilitating tissue repair and regeneration. Exosomes derived from specific microbial sources, such as Bacteroides, are also promising therapeutics for SIONFH. miRNA-based strategies that target the PI3K/AKT pathway may be beneficial in the treatment of SIONFH. Current research is investigating the role of specific miRNAs, such as miR-21 and miR-133a, in the modulation of the PI3K/AKT pathway and the effect on SIONFH progression. Although these approaches show preclinical promise, substantial research is needed to validate their translational potential in clinical practice[26].

CONCLUSION

The PI3K/AKT signaling pathway is central to the pathogenesis of SIONFH and is involved in multiple cellular processes. GCs disrupt this pathway in various bone-related cell types via direct and indirect mechanisms, significantly influencing the pathological progression of SIONFH. Specifically, GCs suppress PI3K/AKT signaling in osteoblasts, resulting in increased apoptosis, reduced proliferation and differentiation, and impaired bone matrix synthesis. Although the mechanisms of GC action in osteoclasts remain controversial, GCs likely promote osteoclast formation and activity through PI3K/AKT pathway modulation, thereby exacerbating bone resorption. GCs alter the differentiation of BMSCs by interfering with the PI3K/AKT pathway, which shifts BMSCs toward adipogenic lineages. GCs also directly impair PI3K/AKT signaling in vascular endothelial cells, reducing vascular endothelial growth factor secretion and compromising vascular integrity. These multilevel and multicellular pathophysiological changes, including osteocyte apoptosis, reduced bone formation, increased bone resorption, and microcirculatory dysfunction, are key drivers of SIONFH progression and highlight the PI3K/AKT pathway as a promising therapeutic target.

Further research into the role of the PI3K/AKT pathway in SIONFH is essential. Future studies should focus on the complex interactions between the PI3K/AKT pathway and other signaling cascades, such as Wnt and mitogen-activated protein kinase, during SIONFH progression. This could help identify precise targets for combination therapies. Furthermore, developing specific and safe modulators of the PI3K/AKT pathway, including agonists and antagonists, requires systematic evaluation in preclinical models and clinical trials to determine efficacy and safety. Exploring combination therapies that target the PI3K/AKT pathway and treatments like anti-resorptive agents, cell-based therapies (e.g., MSCs or their exosomes), and physical interventions may achieve synergistic effects and optimize treatment outcomes in SIONFH. Ultimately, advancing personalized therapies for SIONFH by leveraging a deeper understanding of PI3K/AKT regulatory mechanisms and tailoring interventions to individual pathological and genetic profiles will be crucial for improving treatment precision and effectiveness.