The musculoskeletal system consists of three major, tightly coordinated components: skeletal tissue, which provides structural support and enables smooth movement using synovial joints, muscular tissue, which generates force, and tendinous connective tissue, which transmits to the skeleton the forces generated during muscle contraction. These three elements converge in bone ridges, projections of the bone that serve as anchoring points for muscles, attached to the skeleton via tendons.
The skeleton is, therefore, subjected to mechanical forces applied by the tendon-muscle unit, creating a complex and dynamic physical environment. These mechanical forces have long been known to affect skeleton formation; however, the exact nature of their involvement and the underlying regulatory mechanisms are still obscure.
To study skeletogenesis in the context of the musculoskeletal system development, we concentrate on two main questions: 1) The role of the musculature in joint formation; 2) The contribution of muscles and tendons to bone ridge formation.
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One of the challenging tasks the forming organ is faced with is the need to synchronize its development with that of the vasculature, in order to ensure sufficient gas exchange and nutrient supply. Organs such as lung, liver, kidney and pancreas develop with vasculature that is embedded within them. However, organogenesis may also take place in the absence of embedded vasculature, as in the case of the embryonic midline, including the notochord, neuronal tube, heart valves and cornea. The limb bud is intially vascularized throughout; however, when skeletogenesis begins, the vasculature is subjected to extensive remodeling that leaves the forming skeleton avascular. This intriguing phenomenon of segregation prompted us to study two questions. The first regards the mechanism that regulates the segregation between the forming skeleton and the vasculature and, yet, patterns the vasculature in the vicinity to ensure efficient metabolism. The second question regards the mechanism that enables mesenchymal differentiation into chondrocytes to take place in hypoxic niches.
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