Extracellular Matrix Remodeling and Glycoprotein Biomarkers Across Osteoarthritis, Rheumatoid Arthritis, and Temporomandibular Disorders: A Systematic Review and Integrative Analysis.

Osteoarthritis (OA), rheumatoid arthritis (RA), and temporomandibular disorders (TMDs) are heterogeneous joint diseases whose pathophysiology involves inflammation, tissue degeneration, and progressive functional decline. Although their etiologies differ, these conditions display overlapping molecular mechanisms related to extracellular matrix (ECM) remodeling, proteolytic activity, and immune signaling. This systematic review synthesizes current evidence on glycoprotein-associated and proteomic biomarkers identified in synovial fluid and saliva, predominantly derived from protein-level studies, while also evaluating the limited data on glycosylation-specific changes. Using PRISMA guidelines, thirty-eight studies met the review-level eligibility criteria. A structured molecular dataset derived from 20 of these studies was examined through integrative bioinformatics workflows, including network construction, topology analysis, Gene Ontology enrichment, UpSet intersection analysis, and pathway analysis. The analyses revealed a literature-derived disease-protein network characterized by recurrently reported extracellular matrix proteins and matrix metalloproteinases, together with enrichment of collagen-remodeling and regulated proteolytic pathways. Pathway enrichment further indicated shared mechanisms involving ECM regulation, growth-factor signaling, platelet activation, and inflammatory responses based on pathway enrichment. Glycoproteins, particularly proteoglycan 4 (PRG4), together with fibronectin (FN1), cartilage oligomeric matrix protein (COMP), and aggrecan (ACAN), were recurrently represented within the shared OA-RA protein set and were associated with extracellular matrix organization and inflammatory processes. This systematic review synthesizes protein-level biomarker evidence involving experimentally annotated glycoproteins and separately evaluates studies that directly characterized glycan or glycosylation changes. Protein-level network, overlap, and enrichment analyses identified recurrent extracellular matrix remodeling and regulation of extracellular proteolysis, particularly across OA and RA. These analyses describe disease-associated occurrence of glycoproteins and do not by themselves demonstrate altered glycosylation. Direct glycan-level characterization was available in only 5 of the 38 included studies and was largely restricted to O-glycan alterations involving proteins such as PRG4 and MMP3, underscoring the limited availability of glycosylation-specific evidence. Overall, ECM remodeling and the regulation of extracellular proteolysis emerged as the main shared molecular themes across OA and RA. Comparisons involving TMD remained exploratory because of the small evidence base and the predominance of salivary samples, which prevents separation of disease-related from biofluid-related effects. The complementary use of synovial fluid and salivary biomarkers, although requiring validation through paired-sample studies, may facilitate the development of non-invasive diagnostic and monitoring strategies.