Abstract
Osteonecrosis of the femoral head (ONFH) primarily results from ischemia/hypoxia to the femoral head, and one of the cellular manifestations is the endoplasmic reticulum (ER) stress. To understand possible linkage of ischemic osteonecrosis to the ER stress, a surgery-induced animal model was employed and salubrinal was administered to evaluate the role of ER stress. Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eIF2α, and it can suppress cell death from the ER stress at a proper dose. The results indicated that the ER stress was associated with ONFH and salubrinal significantly improved ONFH-induced symptoms such as osteonecrosis, bone loss, reduction in vessel perfusion, and excessive osteoclastogenesis in the femoral head. Salubrinal also protected osteoblast development by upregulating the levels of ATF4, ALP and RUNX2, and it stimulated angiogenesis of endothelial cells through elevating ATF4 and VEGF. Collectively, the results support the notion that the ER stress is an important pathological outcome in the surgery-induced ONFH model, and salubrinal improves ONFH symptoms by enhancing angiogenesis and bone healing via suppressing the ER stress.
Highlights
The endoplasmic reticulum (ER) is a cellular organelle for modifying, folding, and transporting various proteins[1]
Interruption of the blood supply to the femoral head is a prime cause of ONFH induction[31]
As reported in the previous ONFH studies[12, 16], the results are consistent with significant bone loss in the femoral head
Summary
The endoplasmic reticulum (ER) is a cellular organelle for modifying, folding, and transporting various proteins[1]. Following the accumulation of misfolded proteins, PERK is activated after dissociation of glucose-regulated protein 78 (GRP78) and attenuates protein synthesis by phosphorylating eIF2α. In response to the prolonged and unmitigated ER stress, CHOP may induce apoptosis by stimulating pro-apoptotic factors (e.g., death receptor 5, DR5) and blocking anti-apoptotic B cell CLL/lymphoma 2 (BCL-2)[26]. Salubrinal is known to regulate bone metabolism by elevating phosphorylated eIF2α (p-eIF2α) and activating transcription factors such as ATF427. We have recently demonstrated that the ER stress plays a key role in the pathogenesis of disuse osteoporosis, and salubrinal attenuates unloading-induced bone loss by altering the proliferation and differentiation of osteoblasts and osteoclasts[30]. We employed a rat model of surgically induced ONFH, and evaluated angiogenesis and bone remodelling by examining fates of endothelial cells, osteoclasts, and osteoblasts
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