title: Transmembrane protein 64 reciprocally regulates osteoblast and adipocyte differentiation by modulating Wnt/β-catenin signaling.
abstract: Age-related osteoporosis is associated with a reciprocal decrease in bone formation and an increase in adiposity in the bone marrow niche. We previously reported Transmembrane protein 64 (Tmem64) to be an important regulator of osteoclast function; however, its precise role in osteoblasts has not yet been established. Here, we showed that ablation of the Tmem64 gene in mice resulted in markedly increased osteoblast and reduced adipocyte differentiation from bone marrow-derived stromal cells (BMSCs). Conversely, Tmem64 overexpression inhibited osteogenesis and accelerated adipogenesis. Furthermore, BMSCs isolated from Tmem64 knockout mice formed a greater number of colony-forming unit-osteoblasts and a lower number of colony-forming unit-adipocytes than the wild type controls. Mechanistically, the expression level of β-catenin, the key Wnt signaling molecule, increased significantly, and its nuclear translocation was enhanced in Tmem64-deficient cells. Introduction of Tmem64 significantly suppressed β-catenin-mediated transcriptional activity in an in vitro co-transfection experiment as well as during an in vivo experiment involving BAT-Gal reporter mice. These results demonstrate that Tmem64 plays an important role in the regulation of mesenchymal lineage allocation by modulating Wnt/β-catenin signaling.
authors.affiliation: Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 500-757, Republic of Korea. Electronic address: bcfrank@chonnam.ac.kr.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Jeong
authors.affiliation: TKM-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Daejeon, 305-811, Republic of Korea.
authors.forename: Tae Soo
authors.initials: TS
authors.lastname: Kim
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Oral Microbiology and Immunology, College of Dentistry and Center for Metabolic Function Regulation (CMFR), Wonkwang University, Iksan 570-749, Republic of Korea.
authors.forename: Seoung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104, USA. Electronic address: ychoi3@mail.med.upenn.edu.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis; D047495:PPAR gamma / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D008565:Membrane Proteins; D047495:PPAR gamma; C583521:Tmem64 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Adipocyte; Differentiation; Osteoblast; Tmem64; Wnt/β-catenin