Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice

Abstract

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)–PGE-2 (prostaglandin E2)–HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2−/−) mice were subjected to micro–computed tomography and histological examinations. Compared with their WT littermates, COX-2−/− mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

Identification and Validation of Potential Ferroptosis-Related Genes in Glucocorticoid-Induced Osteonecrosis of the Femoral Head

“…Xu et al [ 39 ] demonstrated that over-expressed HIF-1α resisted Dex-induced apoptosis in a hypoxic environment. Implantation of bone marrow mesenchymal stem cellsoverexpressing HIF-1α into femoral heads of GIONFH mice significantly reduced osteonecrotic areas and enhanced bone repair [ 40 ]. Sun et al [ 41 ] found that Dex induces osteoblast apoptosis via theFoxO signaling pathway.…”

Identification of hub genes and therapeutic drugs in osteonecrosis of the femoral head through integrated bioinformatics analysis and literature mining

“…Zheng et al 17 figured out that COX-2 enhanced osteogenic activity in rats. Zhang et al 18 reported that glucocorticoid induced ONFH via the COX-2-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis. They found that dexamethasone repressed COX-2 expression, thereby reducing HIF-1α expression in femoral heads.…”

Applications of Engineered Skin Tissue for Cosmetic Component and Toxicology Detection

“…For example, 2D skin multitype cells are cultured in the laboratory and they tend to adhere to flat surfaces. This traditional culture method depletes growth media and metabolic wastes, which may result in cell death, nutrient depletion, and damage to the environment in which they are grown, thus preventing complete cell function 12 – 16 . It also does not adequately consider the influence of the three-dimensional (3D) microenvironment under natural physiological conditions on its internal response and affects dose effectiveness and dose toxicity prediction data 17 .…”