Signaling pathways affected by mutations causing osteogenesis imperfecta.

Abstract Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process. Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFβ-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.