title: Role of diabetes- and obesity-related protein in the regulation of osteoblast differentiation.
abstract: Although thyroid hormone (TH) is known to exert important effects on the skeleton, the nuclear factors constituting the TH receptor coactivator complex and the molecular pathways by which TH mediates its effects on target gene expression in osteoblasts remain poorly understood. A recent study demonstrated that the actions of TH on myoblast differentiation are dependent on diabetes- and obesity-related protein (DOR). However, the role of DOR in osteoblast differentiation is unknown. We found DOR expression increased during in vitro differentiation of bone marrow stromal cells into osteoblasts and also in MC3T3-E1 cells treated with TH. However, DOR expression decreased during cellular proliferation. To determine whether DOR acts as a modulator of TH action during osteoblast differentiation, we examined whether overexpression or knockdown of DOR in MC3T3-E1 cells affects the ability of TH to induce osteoblast differentiation by evaluating alkaline phosphatase (ALP) activity. ALP activity was markedly increased in DOR-overexpressing cells treated with TH. In contrast, loss of DOR dramatically reduced TH stimulation of ALP activity in MC3T3-E1 cells and primary calvaria osteoblasts transduced with lentiviral DOR shRNA. Consistent with reduced ALP activity, mRNA levels of osteocalcin, ALP, and Runx2 were decreased significantly in DOR shRNA cells. In addition, a common single nucleotide polymorphism (SNP), DOR1 found on the promoter of human DOR gene, was associated with circulating osteocalcin levels in nondiabetic subjects. Based on these data, we conclude that DOR plays an important role in TH-mediated osteoblast differentiation, and a DOR SNP associates with plasma osteocalcin in men.
authors.affiliation: Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California 92357, USA.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Linares
authors.forename: Weirong
authors.initials: W
authors.lastname: Xing
authors.forename: Hans
authors.initials: H
authors.lastname: Burghardt
authors.forename: Bernhard
authors.initials: B
authors.lastname: Baumgartner
authors.forename: Shin-Tai
authors.initials: ST
authors.lastname: Chen
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C501283:TP53INP2 protein, human; D015675:Osteocalcin