Proteome‐wide profiling reveals dysregulated molecular features and accelerated aging in osteoporosis: A 9.8‐year prospective study

Abstract

The role of circulatory proteomics in osteoporosis is unclear. Proteome‐wide profiling holds the potential to offer mechanistic insights into osteoporosis. Serum proteome with 413 proteins was profiled by liquid chromatography–tandem mass spectrometry (LC–MS/MS) at baseline, and the 2nd, and 3rd follow‐ups (7704 person‐tests) in the prospective Chinese cohorts with 9.8 follow‐up years: discovery cohort ( n = 1785) and internal validation cohort ( n = 1630). Bone mineral density (BMD) was measured using dual‐energy X‐ray absorptiometry (DXA) at follow‐ups 1 through 3 at lumbar spine (LS) and femoral neck (FN). We used the Light Gradient Boosting Machine (LightGBM) to identify the osteoporosis (OP)‐related proteomic features. The relationships between serum proteins and BMD in the two cohorts were estimated by linear mixed‐effects model (LMM). Meta‐analysis was then performed to explore the combined associations. We identified 53 proteins associated with osteoporosis using LightGBM, and a meta‐analysis showed that 22 of these proteins illuminated a significant correlation with BMD ( p < 0.05). The most common proteins among them were PHLD, SAMP, PEDF, HPTR, APOA1, SHBG, CO6, A2MG, CBPN, RAIN APOD, and THBG. The identified proteins were used to generate the biological age (BA) of bone. Each 1 SD‐year increase in KDM‐Proage was associated with higher risk of LS‐OP (hazard ratio [HR], 1.25; 95% CI, 1.14–1.36, p = 4.96 × 10 ⁻⁰⁶), and FN‐OP (HR, 1.13; 95% CI, 1.02–1.23, p = 9.71 × 10 ⁻⁰³). The findings uncovered that the apolipoproteins, zymoproteins, complements, and binding proteins presented new mechanistic insights into osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.

Abstract

Serum proteomics offers potential insight into accelerated aging in osteoporosis. Osteoporosis is commonly referred to as an aging disorder characterized by decreased bone mineral density (BMD) and an elevated risk of fractures. Using longitudinal serum proteomics analyses with 413 protein species covering various protein classes in a population‐based study, we found that the proteins of apolipoproteins, zymoprotein, coagulation, immunoglobulins, complement, and binding proteins may be the potential therapeutic targets for osteoporosis. Serum proteomics could be a crucial indicator for evaluating bone aging.