Homogentisic acid affects human osteoblastic functionality by oxidative stress and alteration of the Wnt/β-catenin signaling pathway

J Cell Physiol. 2020 Oct;235(10):6808-6816. doi: 10.1002/jcp.29575. Epub 2020 Jan 28.

Abstract

Alkaptonuria (AKU) is a rare disease correlated with deficiency of the enzyme homogentisate 1,2 dioxygenase, which causes homogentisic acid (HGA) accumulation. HGA is subjected to oxidation/polymerization reactions, leading to the production of a peculiar melanin-like pigmentation (ochronosis) after chronic inflammation, which is considered as a triggering event for the generation of oxidative stress. Clinical manifestations of AKU are urine darkening, sclera pigmentation, early severe osteoarthropathy, and cardiovascular and renal complication. Despite major clinical manifestations of AKU being observed in the bones and skeleton, the molecular and functional parameters are so far unknown in AKU. In the present study, we used human osteoblasts supplemented with HGA as a AKU cellular model. We observed marked oxidative stress, and for the first time, we were able to correlate HGA deposition with an impairment in the Wnt/β-catenin signaling pathway, opening a range of possible therapeutic strategies for a disease still lacking a known cure.

Keywords: AB_258242 AB_90264; AB_303014; AB_331729; AB_569332; SCR_014246; alkaptonuria; bone diseases; osteoblast; oxidative stress; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaptonuria / metabolism
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Cells, Cultured
  • Homogentisic Acid / pharmacology*
  • Humans
  • Inflammation / metabolism
  • Melanins / metabolism
  • Ochronosis / metabolism
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects*
  • Pigmentation / drug effects
  • Signal Transduction / drug effects
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • Melanins
  • beta Catenin
  • Homogentisic Acid