Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis

David Mellis, Katherine A. Staines, Silvia Peluso, Ioanna Ch Georgiou, Natalie Dora, Malgorzata Kubiak, Rob van’t Hof, Michela Grillo, Colin Farquharson, Elaine Kinsella, Anna Thornburn, Stuart H. Ralston, Donald M. Salter, Natalia A. Riobo-Del Galdo, Robert E. Hill, Mark Ditzel

Research output: Contribution to journalArticlepeer-review


Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.

Original languageEnglish
Article numbere1009275
Number of pages25
JournalPLoS Genetics
Issue number4
Publication statusPublished - 5 Apr 2021

Bibliographical note

Publisher Copyright:
© 2021 Mellis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: MD is supported by a University of Edinburgh Chancellor’s Fellowship and funding from a Carnegie Research Incentive Grant (70356); BH by an MRC University Unit grant MM_UU_00007/8; NARD-G by the NIH (1R01GM088256) and a BBSRC project grant (BB/S01716X/1); KS by the MRC (MR/R022240/2) and CF by BBSRC through an Institute Strategic Programme Grant Funding (BB/J004316/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


  • Hedgehog signaling
  • Knee joints
  • chondrocytes
  • PKA signaling cascading
  • Cartilage
  • Signal processing
  • Tendons
  • Ossification


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