Insights on biology and pathology of HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB pathways in osteoarthritis

Curr Pharm Des. 2012;18(22):3293-312. doi: 10.2174/1381612811209023293.


Osteoarthritis (OA) constitutes a major health problem. Different signaling pathways are involved that impair homeostasis, but the cross-talk between them (although well investigated and partly understood), remains unclear. HIF-1α promotes chondrocyte differentiation and survival, while HIF-2α coactivates with β-catenin and NF-κB pathways to promote chondrocyte apoptosis and endochondral ossification. Depending on the ALK1/ALK5 ratio in chondrocytes, the TGFβ pathway can play an anabolic or catabolic role. TGFβ1 can activate the β-catenin signaling pathway via ALK5, Smad3, PI3K, and PKA pathways. The mediator Axins balance TGF-β and Wnt/β-catenin signaling during chondrocyte proliferation and maturation. However, the biological functions of Wnt/β-catenin signaling are still controversial. Both excessive and insufficient β-catenin levels may impair the homeostasis of articular chondrocytes by enhancing pathological maturation and apoptosis, respectively; loss- and gain-of-functions of β-catenin cause apoptosis at the center of the joint and chondrocyte maturation at the periphery, depending on the vascularity. The NF-κB transcription factor can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines. The recent discovery of functional cross-regulation between these pathways has shown complex roles for HIF-1α/HIF-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB signaling pathways in the pathogenesis of OA. This has important implications for potential therapeutic agents directed at these pathways. This review attempts to cover the literature of the past three years dealing with the biology and pathology of the HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB/cytokines signaling pathways in OA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Proteins / metabolism
  • Chondrocytes / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • NF-kappa B / metabolism
  • Osteoarthritis / physiopathology*
  • Osteoarthritis / therapy
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • Transforming Growth Factor beta
  • Wnt Proteins
  • beta Catenin
  • endothelial PAS domain-containing protein 1