TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation.
Aneurysmal bone cyst (ABC) is a pediatric osseous tumor characterized by extensive destruction of the surrounding bone. The molecular mechanisms underlying its pathogenesis are completely unknown. Recent work showed that translocation of the TRE17/USP6 locus occurs in over 60% of ABC cases resulting in TRE17 overexpression. Immature osteoblasts are presumed to be the cell type harboring translocation of TRE17 in at least a subset of ABCs. However, the effects of TRE17 overexpression on transformation and osteoblast function are unknown. TRE17 encodes a ubiquitin-specific protease (USP) and a TBC (TRE2-Bub2-Cdc16) domain that promotes activation of the Arf6 GTPase. Here we report that TRE17 potently inhibits the maturation of MC3T3 pre-osteoblasts in a USP-dependent and Arf6-independent manner. Notably, we find that TRE17 function is mediated through an autocrine mechanism. Transcriptome analysis of TRE17-expressing cells reveals dysregulation of several pathways with established roles in osteoblast maturation. In particular, signaling through the bone morphogenetic protein (BMP) pathway, a key regulator of osteogenesis, is profoundly altered. TRE17 simultaneously inhibits the expression of BMP-4 while augmenting the BMP antagonist, Gremlin-1. Osteoblastic maturation is restored in TRE17-expressing cells by the addition of exogenous BMP-4, thus establishing a functional role for BMP-4 during TRE17-induced transformation. Because bone homeostasis involves a precise balance between the activities of osteoblasts and osteoclasts, our studies raise the possibility that attenuated osteoblast maturation caused by TRE17 overexpression may contribute to the bone loss/destruction observed in ABC.
Lau
Alan W
AW
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Pringle
Lashon M
LM
Quick
Laura
L
Riquelme
Daisy N
DN
Ye
Ying
Y
Oliveira
Andre M
AM
Chou
Margaret M
MM
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D017824:Bone Cysts, Aneurysmal / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D017077:Culture Media, Conditioned / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
D000089982:ADP-Ribosylation Factor 6; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D000469:Alkaline Phosphatase; D010450:Endopeptidases; C556145:USP6 protein, mouse; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse