Every 30 seconds a person suffers an osteoporosis-related bone fracture in the EU, resulting in significant morbidity, mortality, and health-care costs estimated at €36billion annually. Current therapeutics target bone resorbing osteoclasts, but these are associated with severe side effects. Osteoporosis arises when mesenchymal stem cells (MSC) fail to produce sufficient numbers of bone forming osteoblasts. A key regulator of MSC behaviour is physical loading, yet the mechanisms by which MSCs sense and respond to changes in their mechanical environment are virtually unknown. Primary cilia are nearly ubiquitous ‘antennae-like’ cellular organelles that have very recently emerged as extracellular mechano/chemo-sensors and thus, are strong candidates to play a role in regulating MSC responses in bone. Therefore, the objective of this research program is to determine the role of the primary cilium and associated molecular components in the osteogenic differentiation and recruitment of human MSCs in loading-induced bone adaptation. This will be achieved through ground-breaking in vitro and in vivo techniques developed by the applicant. The knowledge generated in this proposal will represent a profound advance in our understanding of stem cell mechanobiology. In particular, the identification of the cilium and associated molecules as central to stem cell behaviour will lead to the direct manipulation of MSCs via novel cilia-targeted therapeutics that mimic the regenerative influence of loading at a molecular level. These novel therapeutics would therefore target bone formation, providing an alternative path to treatment, resulting in an improved supply of bone forming cells, preventing osteoporosis. Furthermore, these novel therapeutics will be incorporated into biomaterials, generating bioactive osteoinductive scaffolds. These advances will not only improve quality of life for the patient but will significantly reduce the financial burden of bone loss diseases in the EU.