The COST Action is envisaged from the perspective of the musculoskeletal system as a key element for healthy aging.

The foundation of this vision is based on the recognition that mobility is a fundamental component of quality of life, health, and independence of individuals as they age. In the elderly, lack or limited mobility is a trigger for the development of chronic conditions like osteoporosis, diabetes, hypertension and coronary heart disease among several others. During the last 10 years whole-exome sequencing and genome-wide association studies (GWAS) have substantially progressed biological insights on the genetic determinants of monogenic and complex traits [1, 2].

This has also been the case in the musculoskeletal field, particularly for the identification of genetic factors of osteoporosis and associated conditions [3]. Knowledge derived from even more comprehensive GWAS bases on sequenced reference panels [4-6], but also knowledge arising from monogenic disorders presenting with alteration of bone mass and fragility [7, 8] are increasingly providing novel insight on the key regulatory mechanisms governing skeletal physiology. Such abundance of genetic discoveries pleas for the creation of a roadmap characterizing the biological pathways underlying musculoskeletal metabolism, highlighting the opportunities to translate these discoveries in clinical applications (i.e. the development of new medications).

Current treatments for osteoporosis reduce fracture risk by only 25-50% [9, 10] and there are concerns regarding side effects and long-term safety. Similarly, patients with osteoarthritis (another limiting locomotor condition) are asymptomatic in the early stages of disease, develop problems only after significant cartilage erosion has occurred and no drugs are available to prevent or delay disease progression. Thus, there is an urgent need to advance understanding of bone and joint disorders and define new molecular pathways that facilitate development of new treatment options. The potential of incorporating genetic information in the search for suitable drug targets has recently been highlighted by a number of studies demonstrating how successful drug mechanisms are predicted by known genetic associations (i.e. the protein product modulated to elicit a clinical response); and how such improved prediction is perceivable across the whole range of the drug development pipeline, from preclinical and clinical phases to launched drugs. One of these studies also showed that the highest degree of genetic support for drug-target indications was related to the musculoskeletal (bone mineral density), metabolic and blood categories. [11] In this context, drug mechanisms with genetic support are shown to succeed twice as often as those without it (from phase I all the way to approval), and that is the case for osteoporosis drugs as illustrated in the same investigation.

Altogether, the aim of this COST Action is bringing together multiple disciplines currently active in the field of musculoskeletal research under a coordinated effort, which allows translating the emerging wealth of genetic discoveries into palpable clinical applications that can help setting the ground for personalized medicine (Figure 1).

Studies of extreme phenotypes in humans have been instrumental in identifying molecular mechanisms underlying rare single gene disorders as well as common and chronic diseases, including diabetes and obesity. Such studies have resulted in novel treatments that revolutionise the lives of affected individuals [12-15]. The genes identified to underlie several bone disorders aggregating in families (identified through Sequencing) are starting to reveal a large overlap in the biologic pathways
affecting monogenic and complex forms of musculoskeletal and other types of conditions [16, 17]. The biologic insight derived from genes identified through monogenic conditions is huge, as they constitute