Collagen secretion and maturation in osteogenesis imperfecta: Systematic review and meta-analysis

Osteogenesis imperfecta (OI) is a rare genetic disorder most often caused by mutation in genes that encode collagen type I. The collagen pathway is a complex process involving collagen folding, secretion and fibril assembly. The underlying mutation of OI causes a cascade effect resulting alterations at all levels of the collagen pathway. The objective of this study is to use knowledge synthesis to quantify the collagen-I folding kinetics, secretion kinetics, crosslinks, fibril diameter and melting temperature. A systematic search in Medline, Ovid and Web of Science, identified 1001 studies reporting on selected outcomes in OI patients. After screening, we included 51 qualitative studies, 8 quantitative and 43 studies for meta-analysis. Meta-analysis of studies with quantitative data was performed using normalized mean difference as a study-level effect size and a random-effects model with the Hunter and Smith with sample size correction. The collagen-I folding half-life dataset included 8 patients across 3 studies and had an effect size of 0.88 (confidence interval (CI) 0.31, 1.46). The collagen secretion half-life dataset included 8 patients across 7 studies and had an effect size of 0.23 (CI: -0.13, 0.59). The collagen crosslink dataset included 44 patients across 2 studies and had an effect size of 0.37 (CI: 0.09, 0.65). The fibril diameter dataset included 168 patients across 11 studies and had an effect size -0.13 (CI: -0.24, 0.02). The melting temperature dataset is expressed as absolute mean difference, it included 85 patients across 26 studies and had an effect size of -2.29 (CI: -3.32, -1.35). These findings show the collagen pathway is altered in OI, beyond the initial mutation. Our study provides new insights into collagen-I pathophysiology in OI, generating new hypotheses regarding the collagen pathway and mediating disease presentation in different tissues and overall severity.