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.

Proteomic Insights into Osteoporosis: Unraveling Diagnostic Markers of and Therapeutic Targets for the Metabolic Bone Disease

“…MS-based proteomics facilitates the identification and quantification of proteins involved in bone metabolism, providing valuable insights into disease mechanisms and potential therapeutic targets. For instance, liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows for the identification of hundreds of proteins in bone tissues and biofluids, uncovering novel biomarkers associated with OP pathogenesis [15][16][17]. Moreover, targeted MS techniques, such as selected reaction monitoring (SRM) and parallel reaction monitoring (PRM), enable precise quantification of specific proteins of interest, offering opportunities for biomarker validation and personalized medicine approaches in OP research [18][19][20].…”

“…Proteomic approaches play a pivotal role in identifying novel therapeutic targets for OP by unraveling the intricate molecular mechanisms underlying bone metabolism [15,133,134]. By analyzing the proteomic landscape of bone tissues, cell cultures, and biofluids, researchers can identify dysregulated proteins and pathways associated with OP pathogenesis.…”