Custom engineered materials can influence the differentiation of human mesenchymal stem cells (MSCs) towards osteoblasts, chondrocytes and adipocytes, through the control of chemistry, stiffness and nanoscale topography. Here we demonstrate that polycaprolactone growth surfaces engineered with disordered (but controlled) 120 nm diameter dots (NSQ50), but not flat surfaces, promote osteogenic conversion of MSCs in the absence of other osteogenic stimuli. Differentiating MSCs on NSQ50 were found to express growth hormone receptors (GH) and stimulation with recombinant human GH (rhGH) further enhanced NSQ50-driven osteogenic conversion of MSCs. This increased osteogenesis coincided with an enhanced ability of GH to activate ERK MAP kinase on NSQ50, but not on flat topology. The importance of ERK for MSC differentiation was demonstrated by using the inhibitor of ERK activation, U0126, which completely suppressed osteogenesis of GH-stimulated MSCs on NSQ50. The ability of GH to activate ERK in MSCs may therefore be a central control mechanism underlying bone development and growth.