{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:15:29Z","timestamp":1790972129264,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2013,4,22]],"date-time":"2013-04-22T00:00:00Z","timestamp":1366588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>\u2003<\/jats:title>\n                    <jats:p>Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR\u2212\/\u2212) in vivo resulted in a significant reduction in bone mineral density by 4.3% to 6.6% in mice 8 to 20 weeks of age compared with FXR+\/+ mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, tartrate-resistant acid phosphatase (TRACP) staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR\u2212\/\u2212 mice compared with FXR+\/+ mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR\u2212\/\u2212 mice compared with FXR+\/+ mice in concert with a significant reduction in type I collagen a1(Col1a1), ALP, and runt-related transcription factor 2 (Runx2) gene expressions. Cultures of bone marrow\u2013derived macrophages from FXR\u2212\/\u2212 mice exhibited an increased number of osteoclast formations and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In female FXR\u2212\/\u2212 mice, although bone mineral density (BMD) was not significantly different from that in FXR+\/+ mice, bone loss was accelerated after an ovariectomy compared with FXR+\/+ mice. In vitro, activation of FXR by bile acids (chenodeoxycholic acid [CDCA] or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and \u03b2-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol (FOH 1%) diet marginally prevented ovariectomy (OVX)-induced bone loss and enhanced bone mass gain in growing C57BL\/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways; ie, bone formation and resorption. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbmr.1961","type":"journal-article","created":{"date-parts":[[2013,4,22]],"date-time":"2013-04-22T12:00:52Z","timestamp":1366632052000},"page":"2109-2121","source":"Crossref","is-referenced-by-count":107,"title":["Positive regulation of osteogenesis by bile acid through FXR"],"prefix":"10.1093","volume":"28","author":[{"given":"Sun Wook","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee Hyun","family":"An","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineKonkuk University HospitalSeoulKorea"},{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Yeon","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineChungbuk National University HospitalCheongjuKorea"},{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Wan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Joo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mijung","family":"Yim","sequence":"additional","affiliation":[{"name":"College of PharmacySookmyung Women's UniversitySeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wook-Young","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Molecular MedicineCell and Matrix Research Institute, Kyungpook National University School of MedicineDaeguKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular MedicineCell and Matrix Research Institute, Kyungpook National University School of MedicineDaeguKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Soo","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineSeoul National University College of MedicineSeoulKorea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,4,22]]},"reference":[{"key":"2024020318352461200_jbmr1961-bib-0001","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/0092-8674(95)90530-8","article-title":"Identification of a nuclear receptor that is activated by farnesol metabolites","volume":"81","author":"Forman","year":"1995","journal-title":"Cell."},{"key":"2024020318352461200_jbmr1961-bib-0002","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.284.5418.1362","article-title":"Identification of a nuclear receptor for bile acids","volume":"284","author":"Makishima","year":"1999","journal-title":"Science."},{"key":"2024020318352461200_jbmr1961-bib-0003","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1126\/science.284.5418.1365","article-title":"Bile acids: natural ligands for an orphan nuclear receptor","volume":"284","author":"Parks","year":"1999","journal-title":"Science."},{"key":"2024020318352461200_jbmr1961-bib-0004","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1124\/pr.58.4.6","article-title":"International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor","volume":"58","author":"Moore","year":"2006","journal-title":"Pharmacol Rev."},{"key":"2024020318352461200_jbmr1961-bib-0005","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/jm0582221","article-title":"Farnesoid X receptor: from structure to potential clinical applications","volume":"48","author":"Pellicciari","year":"2005","journal-title":"J Med Chem."},{"key":"2024020318352461200_jbmr1961-bib-0006","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.molmed.2007.06.001","article-title":"Targeting farnesoid X receptor for liver and metabolic disorders","volume":"13","author":"Fiorucci","year":"2007","journal-title":"Trends Mol Med."},{"key":"2024020318352461200_jbmr1961-bib-0007","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.tibs.2006.08.002","article-title":"FXR, a multipurpose nuclear receptor","volume":"31","author":"Lee","year":"2006","journal-title":"Trends Biochem Sci."},{"key":"2024020318352461200_jbmr1961-bib-0008","doi-asserted-by":"crossref","first-page":"39313","DOI":"10.1074\/jbc.M007998200","article-title":"The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression","volume":"275","author":"Urizar","year":"2000","journal-title":"J Biol Chem."},{"key":"2024020318352461200_jbmr1961-bib-0009","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1172\/JCI25604","article-title":"Farnesoid X receptor is essential for normal glucose homeostasis","volume":"116","author":"Ma","year":"2006","journal-title":"J Clin Invest."},{"key":"2024020318352461200_jbmr1961-bib-0010","doi-asserted-by":"crossref","first-page":"11039","DOI":"10.1074\/jbc.M510258200","article-title":"The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice","volume":"281","author":"Cariou","year":"2006","journal-title":"J Biol Chem."},{"key":"2024020318352461200_jbmr1961-bib-0011","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1073\/pnas.0506982103","article-title":"Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice","volume":"103","author":"Zhang","year":"2006","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2024020318352461200_jbmr1961-bib-0012","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1172\/JCI200419900","article-title":"PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors","volume":"113","author":"Akune","year":"2004","journal-title":"J Clin Invest."},{"key":"2024020318352461200_jbmr1961-bib-0013","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1002\/jbmr.366","article-title":"Osteoblast-targeted overexpression of PPARgamma inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice","volume":"26","author":"Cho","year":"2011","journal-title":"J Bone Miner Res."},{"key":"2024020318352461200_jbmr1961-bib-0014","doi-asserted-by":"crossref","first-page":"33084","DOI":"10.1074\/jbc.M111.235937","article-title":"Activation of liver X receptor (LXR) inhibits receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation in an LXRbeta-dependent mechanism","volume":"286","author":"Remen","year":"2011","journal-title":"J Biol Chem."},{"key":"2024020318352461200_jbmr1961-bib-0015","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1359\/jbmr.090718","article-title":"The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation","volume":"25","author":"Jeong","year":"2010","journal-title":"J Bone Miner Res."},{"key":"2024020318352461200_jbmr1961-bib-0016","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1074\/jbc.M209505200","article-title":"Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation","volume":"278","author":"Zhang","year":"2003","journal-title":"J Biol Chem."},{"key":"2024020318352461200_jbmr1961-bib-0017","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.bone.2011.08.013","article-title":"Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts","volume":"49","author":"Id Boufker","year":"2011","journal-title":"Bone."},{"key":"2024020318352461200_jbmr1961-bib-0018","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.bone.2009.02.012","article-title":"Wnt inhibitory factor (WIF)-1 inhibits osteoblastic differentiation in mouse embryonic mesenchymal cells","volume":"44","author":"Cho","year":"2009","journal-title":"Bone."},{"key":"2024020318352461200_jbmr1961-bib-0019","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/S0092-8674(00)00062-3","article-title":"Targeted disruption of the nuclear receptor FXR\/BAR impairs bile acid and lipid homeostasis","volume":"102","author":"Sinal","year":"2000","journal-title":"Cell."},{"key":"2024020318352461200_jbmr1961-bib-0020","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat Protoc."},{"issue":"2","key":"2024020318352461200_jbmr1961-bib-0021","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1177\/002215549704500215","article-title":"Embedding of bone samples in methyl methacrylate: an improved method suitable for bone histomorphometry, histochemistry, and immunohistochemistry","volume":"45","author":"Erben","year":"1997","journal-title":"J Histochem Cytochem."},{"key":"2024020318352461200_jbmr1961-bib-0022","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res."},{"key":"2024020318352461200_jbmr1961-bib-0023","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.bbadis.2009.04.004","article-title":"Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-gamma-STAT-1 pathway in macrophages","volume":"1792","author":"Renga","year":"2009","journal-title":"Biochim Biophys Acta."},{"key":"2024020318352461200_jbmr1961-bib-0024","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1021\/jm025529g","article-title":"6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity","volume":"45","author":"Pellicciari","year":"2002","journal-title":"J Med Chem."},{"key":"2024020318352461200_jbmr1961-bib-0025","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/S0960-894X(03)00281-6","article-title":"Binding mode of 6ECDCA, a potent bile acid agonist of the farnesoid X receptor (FXR)","volume":"13","author":"Costantino","year":"2003","journal-title":"Bioorg Med Chem Lett."},{"key":"2024020318352461200_jbmr1961-bib-0026","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1194\/jlr.M500473-JLR200","article-title":"Lipids isolated from bone induce the migration of human breast cancer cells","volume":"47","author":"Silva","year":"2006","journal-title":"J Lipid Res."},{"key":"2024020318352461200_jbmr1961-bib-0027","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.tips.2009.08.001","article-title":"Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders","volume":"30","author":"Fiorucci","year":"2009","journal-title":"Trends Pharmacol Sci."},{"key":"2024020318352461200_jbmr1961-bib-0028","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1172\/JCI200419657","article-title":"Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation","volume":"114","author":"Ikeda","year":"2004","journal-title":"J Clin Invest."},{"key":"2024020318352461200_jbmr1961-bib-0029","doi-asserted-by":"crossref","first-page":"6251","DOI":"10.4049\/jimmunol.0803978","article-title":"The bile acid receptor FXR is a modulator of intestinal innate immunity","volume":"183","author":"Vavassori","year":"2009","journal-title":"J Immunol."},{"key":"2024020318352461200_jbmr1961-bib-0030","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s10549-007-9535-6","article-title":"Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation","volume":"107","author":"Journe","year":"2008","journal-title":"Breast Cancer Res Treat."},{"key":"2024020318352461200_jbmr1961-bib-0031","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10549-008-0094-2","article-title":"Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients","volume":"115","author":"Journe","year":"2009","journal-title":"Breast Cancer Res Treat."},{"key":"2024020318352461200_jbmr1961-bib-0032","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.bcp.2012.02.027","article-title":"Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity","volume":"83","author":"Steri","year":"2012","journal-title":"Biochem Pharmacol."},{"key":"2024020318352461200_jbmr1961-bib-0033","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.tips.2007.03.002","article-title":"FXR: a promising target for the metabolic syndrome?","volume":"28","author":"Cariou","year":"2007","journal-title":"Trends Pharmacol Sci."},{"key":"2024020318352461200_jbmr1961-bib-0034","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1126\/science.1072891","article-title":"A natural product that lowers cholesterol as an antagonist ligand for FXR","volume":"296","author":"Urizar","year":"2002","journal-title":"Science."},{"key":"2024020318352461200_jbmr1961-bib-0035","doi-asserted-by":"crossref","first-page":"10214","DOI":"10.1074\/jbc.M209323200","article-title":"Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump","volume":"278","author":"Cui","year":"2003","journal-title":"J Biol Chem."},{"key":"2024020318352461200_jbmr1961-bib-0036","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1001\/jama.290.6.765","article-title":"Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial","volume":"290","author":"Szapary","year":"2003","journal-title":"JAMA."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.1961","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/10\/2109\/56563693\/jbmr1961.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/28\/10\/2109\/56563693\/jbmr1961.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:49:28Z","timestamp":1710326968000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/28\/10\/2109-2121\/7598700"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,4,22]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2013,4,22]]},"published-print":{"date-parts":[[2013,10,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.1961","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,10,1]]},"published":{"date-parts":[[2013,4,22]]}}}