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Understanding the progression of hypertrophy can be crucial in developing effective disease\u2010modifying therapeutics. To clarify this, we investigated biochemical signatures associated with human healthy cartilage and hypertrophic reactivation in human OA cartilage using a multimodal spectroscopic approach. Healthy adult cartilage and OA samples spanning different disease stages were analyzed using ATR\u2010FTIR, XPS, Raman spectroscopy, DMMB and hydroxyproline assays, along with histology. Across all modalities, OA cartilage exhibited distinct molecular features consistent with a hypertrophic\u2010like shift: pronounced GAG depletion, collagen network disruption, loss of collagen\u2010specific spectral peaks, and elevated oxidative modifications in the ECM. Quantitative assays confirmed reduced GAG and total collagen content, aligning with biochemical patterns observed during endochondral maturation. Raman profiles further captured molecular rearrangements linked to matrix mineralization pathways typically associated with hypertrophic differentiation. Histological evaluation validated the progressive ECM disorganization and GAG loss, reinforcing the spectroscopic findings. Overall, these integrated results suggest that in OA, chondrocyte hypertrophy is not merely a passive consequence, but OA reflects a modified reactivation of endochondral ossification.<\/jats:p>","DOI":"10.1002\/mabi.202500467","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T12:18:48Z","timestamp":1768479528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the Role of Cartilage Hypertrophy in Osteoarthritis Progression: A Structural and Biochemical Analysis of Glycosaminoglycan Loss and ECM Integrity"],"prefix":"10.1002","volume":"26","author":[{"given":"Chandrashish","family":"Roy","sequence":"first","affiliation":[{"name":"Regenerative Engineering Laboratory Department of Textile and Fiber Engineering Indian Institute of Technology  New Delhi 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