Laser-generated lotus-topographies were shown to fulfill important requirements of demanded bioactivity: inhibition of biofilms and fibrotic capsule formation and enhanced regeneration. Here, we figure out how the demonstrated marker-specific improved osteogenic differentiation of human adipose-derived stem cells (hASCs) is accomplished. Comparing flat and lotus-structured titanium, the role of the osteogenic signaling pathways via extracellular-signal related kinase (ERK), c-Jun-N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs), and interplay with ERK/p-ERK and bone morphogenic protein (BMP2)/p-Smad signaling are determined. To our knowledge, this interaction has not been analyzed before. Blocking of ERK and JNK suppresses osteogenic markers like alkaline phosphatase (ALP) activity and calcium mineralization independently from the surface. Their functionality requires both transcription factors osterix and Runx2/p-Runx2, and interplay with ERK/p-ERK and BMP2/p-Smad. P38 plays a regulatory role enabling osteogenic differentiation, which depends on the surface design. Its inhibition generally increases ERK/p-ERK cascade resulting in a high extent of Runx2/p-Runx2. Surface dependent BMP2/p-Smad and osterix are activated. The chief cause in enhanced osteogenic differentiation correlates with the improved attachment on the lotus-topography. Therefore, laser-generated lotus-structures present an attractive surface functionalization, finding their application in diverse biomedical applications.