The systematic experiments demonstrated that (i) 20, but not 2, dynes/cm2 shear force increases SCD-1 protein and mRNA expression levels in human MG63 osteosarcoma cells, (ii) Smad1/5 signaling and PPARδ transcription factor mediates SCD-1 upregulation in human MG63 osteosarcoma cells under high shear force stimulation and (iii) gene knockdown of PPARδ and SCD-1 in human MG63 osteosarcoma cells attenuates the differentiation inhibition and promotes much more cell death of high shear force initiation. The gene discussed is SCD; the disease is osteosarcoma.