Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis
Autoři:
David Mellis aff001; Katherine A. Staines aff002; Silvia Peluso aff003; Ioanna Ch. Georgiou aff004; Natalie Dora aff003; Malgorzata Kubiak aff001; Rob van’t Hof aff005; Michela Grillo aff001; Colin Farquharson aff006; Elaine Kinsella aff001; Anna Thornburn aff003; Stuart H. Ralston aff005; Donald M. Salter aff005; Natalia A. Riobo-Del Galdo aff004; Robert E. Hill aff003; Mark Ditzel aff001
Působiště autorů:
Edinburgh CRUK Cancer Research Centre, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
aff001; School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
aff002; MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
aff003; Leeds Institute of Medical Research and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
aff004; Centre for Genomic and Experimental Medicine, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
aff005; Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, United Kingdom
aff006
Vyšlo v časopise:
Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis. PLoS Genet 17(4): e1009275. doi:10.1371/journal.pgen.1009275
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009275
Souhrn
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.
Klíčová slova:
Cartilage – Ankle joints – Hedgehog signaling – Chondrocytes – Knee joints – Signal processing – Tendons – PKA signaling cascade
Zdroje
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