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

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-1 alpha (hypoxia-inducible factor- I alpha) 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-1 alpha 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-1 alpha (Lenti-HIF-1 alpha) resulted in a robust increase in the production of H IF-1 alpha protein. Implantation of BMMSCs overexpressing HIF-1 alpha 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.