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.

Type 2 Diabetes Mellitus Facilitates Shift of Adipose-Derived Stem Cells Ex Vivo Differentiation toward Osteogenesis among Patients with Obesity

“…To suggest a possible mechanism of osteogenesis activation in ADSCs from T2DM patients, we analyzed the expression of collagen I, which is important for normal osteogenesis, and syndecan 1, which supports adipogenesis [ 32 , 33 , 34 ].…”

Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant

“…It remains to be seen if the discovery of more missense pathogenic variants will further uncover more about the milder end of the P3H1 clinical spectrum. Additionally, the severity of P3H1 -related OI might also be influenced by modifying factors and epigenetics, as it is in the case of other OI forms [ 4 , 31 , 32 , 33 , 34 ].…”

“…OI is known to have a frequency of approximately 1:15–20,000, and it is determined that the vast majority of patient cases (~90%) are caused by autosomal dominant pathogenic variants in the collagen type I α 1 chain ( COL1A1 , OMIM#: 120150) and collagen type I α 2 chain ( COL1A2 , OMIM#: 120160) producing collagen type I [ 3 ]. Defects in collagen type I can also be caused by several genes affecting its regulation [ 4 ]; the prevalence of OI forms by recessive genes may be increased in isolated consanguineous populations [ 5 ]. Pathogenic variants in the prolyl 3-hydroxylase 1 ( P3H1 , OMIM#: 610339) gene were discovered in 2006 as a cause of severe recessive OI, genetic type VIII (OMIM#: 610915) [ 3 , 6 ]; although the clinical types 2 and 3 OI are commonly reported, milder cases also exist [ 7 ].…”

Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study

“…All patients genetically diagnosed with OI in the national reference center for the molecular diagnosis of OI in the Amsterdam UMC between December 1991 and April 2021 were eligible for inclusion in this study. Pathogenic OI variants were identified in COL1A1, COL1A2, CRTAP, TMEM38B, IFITM5, CREB3L1, FKBP10, PLOD2, SP7, SERPINF1, P3H1, BMP1 and PPIB ( 3 ). The pathogenic variants in SERPINH1 and KDELR2 were excluded because these genetic variants had been found in the research setting and are not yet in the diagnostic database.…”

“…Type V is characterized by mineralization of the interosseous membrane and hyperplastic callus formation. In the last two decades, new causative genes for OI have been discovered which stimulated the generation of the genetic classification system (types VI – XXI) ( 3 ). Considering that the clinical presentation of the newly discovered genes overlaps the Sillence types, we adhere to the latter classification in this study.…”