Objective: In this study, we examined how epigenetic factors such as the biomechanic environment govern stem cell fate. Furthermore, we hypothesize that bioengineered substrates and high-density cell culture systems are leading keys to control chondrogenic induction of the mesenchymal stem cells (MSCs). Materials and Methods: To test these hypotheses, human adipose derived mesenchymal stem cells (hASCs) were exposed to 1 Pa shear stress and 3 MPa hydrostatic pressure for 60 minutes on chemically designed medical grade HTV silicone rubber, while no slouble growth factors were added to the culture medium. Transcriptional profiles for terminal differentiation markers of hADSCs were monitored by real time PCR analysis of monolayer cultures. Results: Gene expression patterns were dependent on the loading regime used in well controlled in vitro model system. A greater effect on collagen type II (ColII) mRNA expression was observed for in group C and E compared to the control (group A). Upregulation of aggrecan (Agg) mRNA was similar to the observations in ColII expression profiles. Conclusion: Recently MSCs can differentiate into articular cartilage in an aggregate forming culture systems (pellet and micromass), which need culture manipulation and are difficult to use conventional imaging technique. We present a novel method for generation of hASC-derived chondrocytes in monolayer cultures under mechanically defined conditions. By looking at gene expression patterns it could be concluded that Wnt and TGFβ signaling pathways are involved in chondrogenesis caused through imposing the combination of shape changing deviatoric shear stresses and volume changing cyclic hydrostatic pressure. In addition, both hydrostatic pressure and shear stress alone was insufficient to induce chondrogenic response in hASCs cultures. However, the application of shear stress and hydrostatic pressure led to enhanced chondrocyte specific genes.