Connective tissue is a critical component of all organs and has special importance in the musculoskeletal system. In specialist tissues, such as bone, cartilage of muscle an in vascular structures and internal organs there is a mixture of less specialized connective tissue together with the specific tissue and organ specific cellular components. In addition to physiological function there are two other areas in which it plays a central role. Normal embryonic an postnatal growth and development, and tissue repair in response to injury. It has emerged that there are shared pathways, mediators and mechanisms in these different processes and that multifactorial tissue growth factors have an important role. In this way, these proteins can have a profound influence on multiple cell types and provide a mechanistic link in many complex chronic diseases. It is notable that pathways that are perturbed in one chronic disease, such as atherosclerosis or osteoarthritis may be similarly disrupted in different context in conditions such as lung fibrosis or scleroderma. Transforming growth factor beta family members are prototypic examples of this class of protein. This included TGFbeta isoforms but also the related bone morphogenetic (BMP) and activin family of proteins. They share chemical structure and an ability to regulate multiple cell types in a context specific way. In addition, there is remarkable complexity in their regulation with intrinsic inhibitory mechanisms to protect from inappropriate biological activity. Their role in repair means that activation of preformed protein may regulate biological effects. Proteins regulated by the TGFbeta family, such as the CCN family of matricellular proteins and some for the cardinal growth factors and cytokines share properties. There is functional and signaling redundancy and cross talk. Conceptually it is interesting to envisage dysfunctional networks of cytokines in disease that may be attenuated by extracellular blocking or antagonism. Insights for many areas of developmental biology and pathology have informed about this challenging area of molecular medicine.
Disclosure of Interest C. Denton Grant/research support from: Inventiva, CSL Behring, GSK, Bayer, Consultant for: GSK, Actelion, Inventiva, Roche
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