Inhibition of HIF‑1α restrains fracture healing via regulation of autophagy in a rat model

Abstract

It has been demonstrated that bone fracture is associated with the activation of autophagy, and upregulation of autophagy could promote fracture healing. Previous study by our group demonstrated that activating the HIF-1α pathway via administration of cobalt (II) chloride (CoCl 2 ) could promote fracture healing in vivo. However, the role of hypoxia-inducible factor-1α (HIF-1α) in autophagy remains unknown. In the current study, rats were divided into two groups following tibial fracture and treated with echinomycin or dimethyl sulfoxide (DMSO). Rats were sacrificed at 7, 14, 28 and 42 days after fracture. The evaluation of fracture healing was performed by micro-computed tomography. In addition, the effects of echinomycin on microtubule-associated protein 1 light chain 3 (LC3 II), runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), Unc-51-like autophagy activating kinase 1 (ULK1) and P62 were detected at the mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results demonstrated that the expression of LC3 II was markedly decreased following systemic administration of echinomycin (0.05 mg/kg every other day for 42 days, intraperitoneally). Furthermore, the levels of Runx2, ALP and ULK1 were decreased, while those of P62 were increased, at the mRNA and protein levels in rats treated with echinomycin in vivo. In summary, the current study suggested that HIF-1α may serve an important role in fracture healing via the downregulation of autophagy.

Chronic Intermittent Hypobaric Hypoxia Enhances Bone Fracture Healing

“…HIF-1α is a master regulator of oxygen homeostasis, and its expression was induced by hypoxia ( 41 ). Reports claimed that increased expression of HIF-1α is observed in the early stage of bone regeneration ( 42 , 43 ), suggesting that the expression level of HIF-1α is associated with fracture healing ( 40 , 44 ). Our results revealed that CIHH treatment might promote fracture healing through up-regulating HIF-1α.…”

Study on the Mechanism of Qigu Capsule in Upregulating NF-κB/HIF-1α Pathway to Improve the Quality of Bone Callus in Mice at Different Stages of Osteoporotic Fracture Healing

“…Moreover, autophagy is believed to be a HIF-1 α -dependent adaptive metabolic response to hypoxia [ 37 – 39 ]. Qiao et al reported that HIF-1 α might play an essential role in fracture healing by upregulating osteocyte autophagy [ 22 ]. The effect of OG on local osteocyte autophagy in fracture was observed in the present study.…”

“…Under hypoxia conditions, HIF-1 α can promote the expressions of runt-related transcription factor 2 (Runx2), bone alkaline phosphatase (BALP), and bone Gla protein (BGP) and regulate bone formation by enhancing the bone formation function of osteoblasts [ 20 ]. At the fracture end, HIF-1 α regulates osteocyte autophagy to promote fracture healing [ 21 , 22 ]. Nuclear factor kappa-B (NF- κ B), which is often activated in inflammatory diseases, is an inflammatory transcription factor [ 23 , 24 ].…”

Regulation of Osteoblast Autophagy based on PI3K/AKT/mTOR Signaling Pathway Study on the Effect of β-ecdysterone on Fracture Healing

“…Li [13] reported that the femoral fracture healing in rat model was signi cantly promoted by curcumin by activating autophagy. Qiao [14] reported that the fracture healing in a rat model was restrained by inhibiting HIF-1α through suppressing autophagy. Therefore, the activation of autophagy contributes to the progression of fracture healing.…”