Latest Advances in Structural Insights and Quantification Techniques for Type I Collagen Biomarkers: A path toward standardization?

With an aging population, the demand for sensitive and specific biomarkers to assess bone turnover has surged. Bone turnover involves 2 key processes: bone formation, during which Type I procollagen is cleaved into Type I collagen and subsequently mineralized into bone, and bone resorption, during which Type I collagen is demineralized and degraded into peptides by cathepsin K. To identify biomarkers that accurately reflect these processes, extensive efforts have been made to characterize the peptides generated during both formation and resorption. Over the years, numerous biomarkers have been discovered for various disorders. However, despite their clinical utility, many of these markers lack specificity. This is due to factors such as the degradation of trimers into monomers, the coexistence of multiple peptide species arising from the unpredictable cleavage of Type I collagen/procollagen by cathepsin K and metalloproteinases, and the lack of assay standardization. Standardization is further hindered by the incomplete characterization of many of these peptides. For accurate assay development, a gold-standard technique like LC-MS/MS is essential, requiring full peptide characterization during method development. This review aims to present recent advances in the characterization of Type I collagen-derived peptides, providing a foundation for improved biomarker standardization and application in clinical practice.