Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis

Int J Mol Sci. 2019 Sep 19;20(18):4653. doi: 10.3390/ijms20184653.

Abstract

Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low secretory and an activated, pro-inflammatory and anti-resorptive subclass producing high quantities of IL-6, PGE2, and osteoprotegerin, but low levels of RANKL, thus acting as putative effectors of subchondral bone sclerosis. Wnt agonists, Wnt5a, Wisp-1 initiate excessive bone remodeling, while Wnt3a and 5a simultaneously cause loss of proteoglycans and phenotype shift in chondrocytes, with decreased expression of COL2A, aggrecan, and Sox-9. Sclerostin, a Wnt antagonist possesses a protective effect for the cartilage, while DKK-1 inhibits VEGF, suspending neoangiogenesis in the subchondral bone. Experimental conditions mimicking abnormal mechanical load, the pro-inflammatory milieu, but also a decreased OPG/RANKL ratio in the cartilage, trigger chondrocyte apoptosis and loss of the matrix via degradative matrix metalloproteinases, like MMP-13 or MMP-9. Hypoxia, an important cofactor exerts a dual role, promoting matrix synthesis via HIF-1α, a Wnt silencer, but turning on HIF-2α that enhances VEGF and MMP-13, along with aberrant collagen expression and extracellular matrix deterioration in the presence of pro-inflammatory cytokines.

Keywords: Wnt signaling; bone-cartilage interface; osteoarthritis.

Publication types

  • Review

MeSH terms

  • Animals
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology
  • Cartilage, Articular / metabolism*
  • Cartilage, Articular / pathology
  • Humans
  • Osteoarthritis / metabolism*
  • Osteoarthritis / pathology
  • Osteoprotegerin / metabolism*
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*

Substances

  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFRSF11B protein, human
  • TNFSF11 protein, human
  • Wnt Proteins