Final Report Summary - TENDONTOBONE (The mechanisms that underlie the development of a tendon-bone attachment unit)
The attachment of the relatively soft tendon to the much harder bone creates a huge challenge for the developing musculoskeleton. The forces generated by muscle contraction are transferred through this physical interface to the skeleton, creating high concentration of load at the attachment site. Evolution has solved this engineering problem by forming the enthesis, a unique transitional tissue that exhibits a gradient of cellular and extracellular properties through its length. Despite the ingenuity of this solution, the enthesis is still a weak point that is susceptible to injury and disease and, because of the complexity of this tissue, efforts to develop regeneration-based treatments have thus far failed.
Although the connection of muscles via tendons to the skeleton is essential for musculoskeletal function, little is known on how this connection occurs. To fill this gap in knowledge, we have devoted our project to investigating enthesis development by combining methods of molecular, cell and developmental biology, mouse genetics and computer vision. Our findings shed light on fascinating cellular and molecular mechanisms involved in enthesis development and maturation, such as replacement of cell population, the creation of a new cell fate by activation of two genetic programs, and developmental modularity, as well as on the role of mechanoregulation in these processes.
These findings promote a more integrative and holistic view of the musculoskeletal system, underscoring regulatory interactions among different tissues and their coordinated assembly into one functional organ system, and provide insight into general strategies of development and evolution. From a medical perspective, our contribution to the understanding of enthesis development provides the basis for development of new therapeutic and regenerative approaches for common pathologies and injuries affecting this vulnerable tissue.
Although the connection of muscles via tendons to the skeleton is essential for musculoskeletal function, little is known on how this connection occurs. To fill this gap in knowledge, we have devoted our project to investigating enthesis development by combining methods of molecular, cell and developmental biology, mouse genetics and computer vision. Our findings shed light on fascinating cellular and molecular mechanisms involved in enthesis development and maturation, such as replacement of cell population, the creation of a new cell fate by activation of two genetic programs, and developmental modularity, as well as on the role of mechanoregulation in these processes.
These findings promote a more integrative and holistic view of the musculoskeletal system, underscoring regulatory interactions among different tissues and their coordinated assembly into one functional organ system, and provide insight into general strategies of development and evolution. From a medical perspective, our contribution to the understanding of enthesis development provides the basis for development of new therapeutic and regenerative approaches for common pathologies and injuries affecting this vulnerable tissue.