Endoplasmic reticulum stress in steroid-induced osteonecrosis: translational bottlenecks and targeted therapeutic...

Area of Science:

• Orthopedics
• Molecular Biology
• Pathology

Background:

• Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating orthopedic condition with poorly understood molecular mechanisms.
• Glucocorticoids are a known cause, but the cellular pathways leading to tissue destruction require further elucidation.
• Endoplasmic reticulum stress (ERS) is increasingly recognized as a central player in SONFH pathogenesis.

Purpose of the Study:

• To synthesize current evidence on the role of ERS in SONFH.
• To explore the signaling paradoxes and translational challenges associated with ERS in SONFH.
• To propose novel therapeutic strategies for SONFH.

Main Methods:

• Comprehensive literature review of ERS mechanisms in SONFH.
• Analysis of molecular pathways including PERK-CHOP, mTOR, and HIF-1α.
• Evaluation of microenvironmental factors and lipid metabolism interactions.
• Assessment of translational barriers in animal models.

Main Results:

• ERS induces osteoblast apoptosis via the PERK-CHOP pathway and inhibits endothelial regeneration by suppressing mTOR signaling.
• ERS exhibits heterogeneous effects, promoting chondrocyte matrix degradation via HIF-1α stabilization.
• ERS worsens intraosseous ischemia through a positive feedback loop with lipid metabolism.
• The 'ischemic island' effect and animal model limitations hinder clinical translation of ERS inhibitors.

Conclusions:

• ERS is a critical mediator of SONFH pathology through diverse cellular and molecular mechanisms.
• Combinatorial approaches using ERS modulators and targeted delivery systems are promising for overcoming therapeutic hurdles.
• Advanced nanocarrier strategies could breach the ischemic barrier, enabling precision joint-preserving therapies for SONFH.