Chondrodysplasias and TGFb signaling

Human chondrodysplasias are a group of conditions that affect the cartilage. It involves the growth, organization and development of the skeleton. The majority of bones in the skeleton are generated through two different mechanisms: the intramembranous and the endochondral ossifications. In the intramembranous process, mesenchymal cells originating from the neural crest and the cephalic mesoderm differentiate into osteoblast cells to form flat bones like cranial vault, maxilla, mandible or clavicles. In the endochondral process, the condensed mesenchymal cells proliferate, and differentiate into chondrocytes. The hyaline chondrocytes are differentiated into hypertrophic chondrocytes, which finally undergo apoptosis following bone matrix deposition. Some cartilage tissues persist within the growth plate positioned between the ossified epiphyses ends and diaphysis of the long bone, allowing continuous postnatal longitudinal bone growth. Transforming growth factor-b (TGFb) is important in chondrogenesis and osteogenesis. TGFbbelongs to a superfamily of related signaling proteins, the cytokines, that regulate a wide variety of biological processes, including cell growth, apoptosis differentiation, migration, extracellular matrix production, angiogenesis, immunity and development. This family also includes activins and bone morphogenetic proteins (BMPs). Those cytokines signal through a well-characterized pathway of transmembrane serine–threonine kinase receptors and intracellular signaling molecules of the SMAD (mothers against DPP) family. Upon activation of Smad proteins by phosphorylation, they accumulate in the nucleus and regulate transcription. The bioavailability of TGFb itself, and thus its activity, is tightly regulated through the extracellular matrix (ECM). Extracellular regulation of TGFb signaling can be observed at levels of the coreceptor (which controls the access of ligands to signaling receptors) or of ECM molecules such as fibrillin (Fibrillin-1 (FBN1)), involved especially in TGFb bioavaibility. TGFb works synergistically with BMPs, depending on the stage of differentiation. In this review, we will focus on the recent TGFb signaling involvement in a specific group of chondrodysplasias, the acromelic dysplasia.