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<p>Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1β (IL-1β)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1β was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1β drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1β as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH progression.</p> Graphical Abstract <p>Necrotic subchondral bone expresses inflammatory cytokines, especially IL-1β, and triggers pathological remodeling of the calcified cartilage zone (CCZ). This remodeling manifests as reduced thickness, matrix demineralization, reduced elastic modulus, and increased porosity. The compromised CCZ disrupts mechanical load distribution at the osteochondral interface, causing abnormal stress accumulation, extracellular matrix dysregulation, and reduced mechanical stabilization in adjacent cartilage, ultimately accelerating degeneration.</p> <p></p>

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Calcified Cartilage Zone Remodeling Induced by IL-1β Derived from Necrotic Subchondral Bone Initiates Cartilage Degeneration in Patients with Glucocorticoids-induced Osteonecrosis of the Femoral Head

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月14日

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  • Pengbo Wang,
  • Limei Shen,
  • Ruitong Yang,
  • Xu Wang,
  • Xiangyu Wang,
  • Yingkang Zhu,
  • Ruiyu Liu

摘要

Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1β (IL-1β)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1β was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1β drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1β as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH progression.

Graphical Abstract

Necrotic subchondral bone expresses inflammatory cytokines, especially IL-1β, and triggers pathological remodeling of the calcified cartilage zone (CCZ). This remodeling manifests as reduced thickness, matrix demineralization, reduced elastic modulus, and increased porosity. The compromised CCZ disrupts mechanical load distribution at the osteochondral interface, causing abnormal stress accumulation, extracellular matrix dysregulation, and reduced mechanical stabilization in adjacent cartilage, ultimately accelerating degeneration.