{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T03:17:40Z","timestamp":1794021460967,"version":"4.8.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Knee osteoarthritis (KOA) is characterized by progressive cartilage degeneration and disruption of extracellular matrix (ECM) homeostasis. Chondrocytes are not a homogeneous or static population during disease progression but exhibit pronounced functional heterogeneity. Although single-cell transcriptomic studies have identified multiple chondrocyte states in osteoarthritic cartilage, how these states dynamically relate to ECM remodeling and disease progression remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated multiple publicly available single-cell RNA sequencing datasets of human knee cartilage to construct a unified cellular atlas and systematically compared chondrocyte states between control and KOA samples. Differential expression analysis, functional enrichment, pseudotime trajectory inference, and cell\u2013cell communication analysis were applied to characterize ECM-related chondrocyte states and their dynamic transitions. Key signaling cues identified from single-cell analyses were further evaluated using\n                      <jats:italic>in vitro<\/jats:italic>\n                      cultured human articular chondrocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed a marked expansion of the previously described reparative chondrocyte population (RepC) in KOA cartilage. Rather than reflecting a simple increase in cell proportion, KOA-associated RepC exhibited enhanced ECM remodeling programs characterized by collagen reorganization and strengthened ECM\u2013cell interactions. Pseudotime analysis positioned RepC downstream of proliferation chondrocytes and near a major branching region toward either regulator chondrocytes with further extension toward fibrocartilage chondrocytes or effector chondrocytes. In KOA, RepC was preferentially represented at mid-to-late pseudotime stages within the reconstructed trajectory framework. Cell\u2013cell communication analysis suggested that RepC showed prominent inferred ECM-related interactions, particularly involving collagen and FN1\u2013integrin pathways. Consistently, FN1 or TGF-\u03b21 stimulation\n                      <jats:italic>in vitro<\/jats:italic>\n                      induced expression of multiple RepC-associated genes and enhanced SMAD2\/3 phosphorylation, recapitulating key features of the RepC state observed in single-cell analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings highlight ECM remodeling features of reparative chondrocytes during KOA and support a state-centric view in which disproportionate representation of reparative states within the pseudotime trajectory framework is associated with maladaptive ECM remodeling in KOA.<\/jats:p>\n                  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