Collagen transport and related pathways in Osteogenesis Imperfecta

Abstract

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.

Fig. 1

Biosynthesis pathway of collagen type I. a Folding and posttranslational modification of the COL1α1 and COL1α2 chains and of the procollagen triple helix takes place in the RER (rough endoplasmic reticulum). These modifications are performed by the CRTAP–P3H3–CYPB and FKBP65–LH2 complexes, turning proline to hydroxyproline and lysine to hydroxylysine respectively. HSP47 is a chaperone protein which assists in the stabilization of the triple helix and its transportation through the ER. The whole process of biosynthesis of type I collagen is calcium-regulated. TRIC-B is one of the channels regulating ER Ca²⁺ flow via IP₃R channel. Ca²⁺ also stabilizes the process of collagen trimerization and foldings. b Anterograde transport of the procollagen triple helix from the ER to the Golgi apparatus via COPII-mediated vesicle transport. Many proteins are involved in the formation of the COPII vesicle such as the SEC23/24 dimer (inner coat), the SEC13/31 dimer (outer coat), SEC12, SAR1, TANGO1 and cTAGE5. TANGO1 and HSP47 facilitate the entering of procollagen in the forming vesicle. SEC12 and in turn SAR1 recruit SEC23/24 dimers to form the inner coat. c Retrograde transport of ER proteins via COPI (α-COP, β’-COP, ε-COP, β-COP, δ-COP, γ-COP and ζ-COP) -mediated vesicle transport. FKBP65 and HSP47 are chaperone proteins which are returned to the ER, assisted by KDELR2 receptors in the Golgi membrane. STX18 and NBAS assist in the arrival and fusion of the COPI vesicles to the ER membrane. d S2P response to ER stress. The cleavage of OASIS activates transcription (TF: transcription factor) of genes involved in the ER stress response pathway; COL1A1 transcription is activated by SMAD4. e Extracellular processing of the procollagen type I triple helix and formation of fibrils and fibers. The C- and N-propeptides are cleaved-off by BMP1 and ADAMTS2, 3 or 14, respectively. After cleavage, the formation of collagen fibrils takes place

Fig. 1

Biosynthesis pathway of collagen type I. a Folding and posttranslational modification of the COL1α1 and COL1α2 chains and of the procollagen triple helix takes place in the RER (rough endoplasmic reticulum). These modifications are performed by the CRTAP–P3H3–CYPB and FKBP65–LH2 complexes, turning proline to hydroxyproline and lysine to hydroxylysine respectively. HSP47 is a chaperone protein which assists in the stabilization of the triple helix and its transportation through the ER. The whole process of biosynthesis of type I collagen is calcium-regulated. TRIC-B is one of the channels regulating ER Ca²⁺ flow via IP₃R channel. Ca²⁺ also stabilizes the process of collagen trimerization and foldings. b Anterograde transport of the procollagen triple helix from the ER to the Golgi apparatus via COPII-mediated vesicle transport. Many proteins are involved in the formation of the COPII vesicle such as the SEC23/24 dimer (inner coat), the SEC13/31 dimer (outer coat), SEC12, SAR1, TANGO1 and cTAGE5. TANGO1 and HSP47 facilitate the entering of procollagen in the forming vesicle. SEC12 and in turn SAR1 recruit SEC23/24 dimers to form the inner coat. c Retrograde transport of ER proteins via COPI (α-COP, β’-COP, ε-COP, β-COP, δ-COP, γ-COP and ζ-COP) -mediated vesicle transport. FKBP65 and HSP47 are chaperone proteins which are returned to the ER, assisted by KDELR2 receptors in the Golgi membrane. STX18 and NBAS assist in the arrival and fusion of the COPI vesicles to the ER membrane. d S2P response to ER stress. The cleavage of OASIS activates transcription (TF: transcription factor) of genes involved in the ER stress response pathway; COL1A1 transcription is activated by SMAD4. e Extracellular processing of the procollagen type I triple helix and formation of fibrils and fibers. The C- and N-propeptides are cleaved-off by BMP1 and ADAMTS2, 3 or 14, respectively. After cleavage, the formation of collagen fibrils takes place