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<p>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction, in which dysregulated chondrocyte apoptosis and impaired autophagy play critical roles, yet the upstream molecular drivers remain incompletely understood. Here, we identify pro-platelet basic protein (PPBP/CXCL7) as a previously unrecognized mediator of cartilage degeneration in OA. PPBP expression was markedly elevated in human OA cartilage, in the destabilization of the medial meniscus (DMM) mouse model, and in IL-1β–stimulated primary chondrocytes. Functional analyses revealed that PPBP overexpression augmented inflammatory and catabolic responses, suppressed autophagy, and promoted chondrocyte apoptosis, whereas PPBP knockdown preserved extracellular matrix homeostasis, enhanced LC3-associated autophagy, and reduced apoptotic cell death. Mechanistically, PPBP activation was associated with increased phosphorylation of PI3K and AKT and concomitant autophagy suppression; conversely, PPBP inhibition reduced PI3K and AKT phosphorylation, restored autophagic activity, and these protective effects were abolished by pharmacological autophagy inhibition using 3-methyladenine. Importantly, intra-articular silencing of PPBP in DMM mice attenuated cartilage erosion, preserved collagen II, reduced MMP13 expression, increased LC3 levels, and decreased chondrocyte apoptosis in vivo. Collectively, these findings establish PPBP as a key regulator of autophagy–apoptosis imbalance in OA chondrocytes and highlight PPBP as a potential therapeutic target for disease-modifying intervention in OA.</p>

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PPBP orchestrates autophagy–apoptosis imbalance to drive cartilage degeneration in osteoarthritis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月30日

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  • Han Zhang,
  • Kehao Hou,
  • Xiao Ma,
  • Guantong Sun,
  • Le Kuai,
  • Tianrui Wang,
  • Yongtao Zhang,
  • Guanhong Chen,
  • Xiaohong Huang,
  • Yingze Zhang

摘要

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction, in which dysregulated chondrocyte apoptosis and impaired autophagy play critical roles, yet the upstream molecular drivers remain incompletely understood. Here, we identify pro-platelet basic protein (PPBP/CXCL7) as a previously unrecognized mediator of cartilage degeneration in OA. PPBP expression was markedly elevated in human OA cartilage, in the destabilization of the medial meniscus (DMM) mouse model, and in IL-1β–stimulated primary chondrocytes. Functional analyses revealed that PPBP overexpression augmented inflammatory and catabolic responses, suppressed autophagy, and promoted chondrocyte apoptosis, whereas PPBP knockdown preserved extracellular matrix homeostasis, enhanced LC3-associated autophagy, and reduced apoptotic cell death. Mechanistically, PPBP activation was associated with increased phosphorylation of PI3K and AKT and concomitant autophagy suppression; conversely, PPBP inhibition reduced PI3K and AKT phosphorylation, restored autophagic activity, and these protective effects were abolished by pharmacological autophagy inhibition using 3-methyladenine. Importantly, intra-articular silencing of PPBP in DMM mice attenuated cartilage erosion, preserved collagen II, reduced MMP13 expression, increased LC3 levels, and decreased chondrocyte apoptosis in vivo. Collectively, these findings establish PPBP as a key regulator of autophagy–apoptosis imbalance in OA chondrocytes and highlight PPBP as a potential therapeutic target for disease-modifying intervention in OA.