ECTS Abstracts (2015) 1 P226

UBR5, an E3 ubiquitin-protein ligase, regulates hedgehog-mediated articular cartilage homeostasis

David Mellis, Michela Grillo, Natalie Dora, Elaine Kinsella, Antonia Sophocleous, Stuart Ralston, Donald Salter, Robert Hill & Mark Ditzel

IGMM, School of Molecular, Genetic and Population Health Sciences, Western General Hospital, University of Edinburgh, Edinburgh, UK.

Our objective was to investigate UBR5’s role in regulating articular cartilage homeostasis. Our work has revealed the N-end Rule Ubiquitin-protein ligase UBR5 as a potent suppressor of osteoarthritis-associated changes in murine articular cartilage (AC). Using Prx-Cre combined with a floxed UBR5 mutant allele we deleted UBR5 function in the developing murine limb buds. Homozygous UBR5 mutant (UBR5mt) limbs appeared morphologically normal, but exhibited reduced Hedgehog signalling (IHH, PTCH1, GLI1) and perturbed expression two master regulators of chondrocyte biology (MSX2 and RUNX2). Six-week-old UBR5mt animals exhibited chondrocyte clustering, massively increased numbers of hypertrophic-like chondrocytes, osteophytes, vascular invasion and cartilage fibrillation (n=6). By 12 weeks of age, UBR5mt animals exhibited dramatic AC loss down to the subchondral bone (n=6). We hypothesise that UBR5 influences stem/progenitor-mediated control of AC homeostasis. Our work in other murine tissues indicates UBR5 as an important regulator of stem/progenitor cell function, with UBR5 being highly upregulated in pericytes, the progenitors of mesenchymal stem cells. Furthermore, we revealed that UBR5 regulates both Indian Hedgehog (IHH) ligand production and signal transduction. IHH-mediated signalling plays a central role in governing stem/progenitor cell function in various tissues, including juvenile and adult bone. Based on IHH’s role in the growth plate, we hypothesise that UBR5 normally functions to promote IHH-mediated suppression of chondrocyte hypertrophy and AC homeostasis. Our current work addresses this hypothesis by (i) utilising Hedgehog pathway agonists and antagonist and (ii) Hedgehog signalling-associated gain-and loss-of-function alleles to modify the UBR5mt AC phenotype. We conclude that UBR5 regulates AC homeostasis and suppresses chondrocyte hypertrophy.

Disclosure: The authors declared no competing interests. This work was supported by The University of Edinburgh.

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