School Seminar Series - Professor Jiake Xu - University of Western Australia

Professor Jiake Xu - University of Western Australia

Uncovering a new case of human malignant osteopetrosis and its mechanistic insights

Disturbances in the molecular machinery that regulate endolysosomal trafficking lead to osteoclast dysfunction and osteopetrosis: a group of clinically and genetically heterogeneous skeletal diseases that share the feature of high bone mass. Human autosomal recessive osteopetrosis (ARO), also called malignant infantile osteopetrosis, is a severe osteoclast-rich form ARO diagnosed at birth and often lethal within 10-years in untreated patients.  Among the genes implicated in ARO, mutations in sorting nexin 10 (SNX10) account for >4% of affected infants. SNX10 is a ‘Phox–homology (PX) domain containing only’ member of the sorting nexin (SNX) family that play essential roles in membrane trafficking via the endocytic pathway. We have identified a patient with a novel mutant, SNX10-R51X, who suffered from severe osteopetrosis and bone marrow occlusion. Consistently, SNX10 knockout mice exhibited severe osteopetrosis and prevented bone loss in collagen-induced arthritic mice. We further demonstrated that SNX10 (-/-) osteoclasts displayed impaired bone-resorption function accompanied by defective F-actin belt formation and integrin β3-Src signalling, and reduced expression of TRAP, CtsK and MMP9 in SNX10 (-/-) osteoclasts. Interestingly, the defective function of SNX10 (-/-) osteoclasts was partially restored by adenovirus - mediated SNX10 overexpression, indicative of its potential application in gene therapy for SNX10 deficiency.  Using bimolecular fluorescence complementation (BiFC) to screen for putative SNX10-interacting partners, we identified that SNX10 interacts with ATG5 and other novel molecules, and co-localizes in the autophagosome pathways. Consistently, knockdown of SNX10 expression leads to impairments in autophagosome maturation and autophagic flux. Further, small molecule screening program in collaboration with Atomwise has identified novel compound candidates that have potential for the inhibition of SNX10 and for the treatment for osteoclast related diseases such as osteoporosis and bone metastasis.   

Speaker bio: 

Prof. Jiake Xu is currently Winthrop Professor, Head of Molecular Laboratory, and Head of the Division of Regenerative Biology, School of Biomedical Sciences, at the University of Western Australia (UWA). He is a founding Fellow, Faculty of Science, the Royal College of Pathologists of Australia, and ex-president of the Australian and New Zealand Orthopaedic Research Society (ANZORS, 2012-2015). He is also Fellow of ASBMR, and Fellow of International Orthopaedic Society.

After completing his PhD studies at UWA in 1994, he carried out his postdoctoral research at Stanford University from 1994 to 1998. He returned to UWA in 1998, and has since undertaken research and teaching in the School of Biomedical Sciences, UWA.

His research interests are in osteoclast biology, molecular cross talks of osteoclast and osteoblast, as well as angiogenic and angiocrine regulation in bone microenvironment, which have significant implication in skeletal disorders. He has published 250 SCI papers as an author, including Nat. Med. Endocr Rev. PNAS, Ann Rheum Dis. JBMR, MCB and JBC. His published work in “osteoclasts”, “RANKL” and “osteolysis”, has been objectively ranked as No. 3, 4 and 22 worldwide by Expertscape (https://expertscape.com/).

He serves in the Editorial Boards of The Journal of Biological Chemistry (JBC), and the Journal of Cellular Physiology (JCP) etc, as well as an Associate Editor of at the Frontiers in Cell and Developmental Biology.

Weblinks

https://research-repository.uwa.edu.au/en/persons/jiake-xu

https://www.linkedin.com/in/jiake-xu-2a416635/?originalSubdomain=au