MIF Plays a Key Role in Regulating Tissue-Specific Chondro-Osteogenic Differentiation Fate of Human Cartilage Endplate Stem Cells under Hypoxia

摘要

Summary Degenerative cartilage endplate (CEP) shows decreased chondrification and increased ossification. Cartilage endplate stem cells (CESCs), with the capacity for chondro-osteogenic differentiation, are responsible for {CEP} restoration. {CEP} is avascular and hypoxic, while the physiological hypoxia is disrupted in the degenerated CEP. Hypoxia promoted chondrogenesis but inhibited osteogenesis in CESCs. This tissue-specific differentiation fate of {CESCs} in response to hypoxia was physiologically significant with regard to {CEP} maintaining chondrification and refusing ossification. MIF, a downstream target of HIF1A, is involved in cartilage and bone metabolisms, although little is known about its regulatory role in differentiation. In CESCs, {MIF} was identified as a key point through which {HIF1A} regulated the chondro-osteogenic differentiation. Unexpectedly, unlike the traditionally recognized mode, increased nuclear-expressed {MIF} under hypoxia was identified to act as a transcriptional regulator by interacting with the promoter of {SOX9} and RUNX2. This mode of HIF1A/MIF function may represent a target for {CEP} degeneration therapy.