Procollagen Trafficking and its Implications in Osteogenesis Imperfecta

Recent discoveries of skeletal dysplasias caused by mutations in COPII coat proteins responsible for a key checkpoint in the secretory pathway have renewed the interest of matrix biologists in procollagen trafficking. Osteogenesis imperfecta (OI) has long been considered a disorder related to malformations or malfunction of type I collagen and its procollagen precursor (type I collagenopathy). However, OI and chondrodysplasia features of patients with mutations in inner COPII coat proteins SEC24D and SEC23A have revealed that procollagen malformations and trafficking defects might cause similar pathology. The goal of this review is to bridge our knowledge of procollagen biosynthesis, secretory protein trafficking, degradative protein trafficking, and genetic defects in skeletal development, in order to understand the pathophysiology of these and related diseases. We argue that folding in the Endoplasmic Reticulum (ER), sorting by COPII-bound proteins at ER exit sites, transport by COPI carriers to Golgi, and autophagy of misfolded molecules are all intimately linked and crucial steps in procollagen homeostasis. Disruptions in these processes by mutations in key regulatory proteins underlie common collagenopathy-like skeletal pathologies in a wide variety of hereditary disorders ranging from OI to lysosomal storage diseases.