{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:39:21Z","timestamp":1791121161151,"version":"4.1.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,2]]},"abstract":"<jats:p>We previously demonstrated that the orphan nuclear receptor, estrogen receptor-related receptor \u03b1 (ERR\u03b1) is highly expressed in osteoblasts and osteoclasts, regulates osteogenesis and expression of osteoblast-associated markers in the rat calvaria cell differentiation system, and is dysregulated in the rat ovariectomy model of postmenopausal osteoporosis. There are conflicting published data on the transcriptional regulation by ERR\u03b1 of the gene for osteopontin (OPN), an extracellular matrix protein required in bone remodeling, and a potential direct target mediating ERR\u03b1 effects in bone. We therefore readdressed OPN gene regulation by ERR\u03b1 in both osteoblastic (rat osteosarcoma ROS17\/2.8 cells) and non-osteoblastic (HeLa) cell lines using a mouse proximal 2\u200akb OPN promoter fragment. A minimal OPN promoter fragment spanning from \u221256 to +9\u200abp is activated in HeLa cells but repressed it in ROS17\/2.8 cells. Adenine scanning mutagenesis revealed the presence of a non-canonical ERR\u03b1 response element in this minimal promoter. Surprisingly, prototypical inactivating mutations in the activation function 2 (AF2) domain or a naturally occurring allelic variant of ERR\u03b1 (ERR\u03b1H408) were all better activators than wild-type ERR\u03b1 in HeLa cells, activities that were generally paralleled by repression in ROS17\/2.8 cells. Finally, we found that the N-terminus of ERR\u03b1 harbors a repressor domain that acts in a cell context-dependent manner. We conclude that OPN is an ERR\u03b1 target gene whose promoter is regulated by ERR\u03b1 in a cell context-dependent manner and that a predicted silencing mutation in AF2 or a more flexible helix 12 increases ERR\u03b1 transcriptional activity, effects with implications for ERR\u03b1 as a therapeutic target in bone.<\/jats:p>","DOI":"10.1677\/jme-07-0114","type":"journal-article","created":{"date-parts":[[2008,1,30]],"date-time":"2008-01-30T13:23:33Z","timestamp":1201699413000},"page":"61-73","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":43,"title":["Estrogen receptor-related receptor \u03b1 (ERR\u03b1) regulates osteopontin expression through a non-canonical ERR\u03b1 response element in a cell context-dependent manner"],"prefix":"10.1530","volume":"40","author":[{"given":"Ralph A","family":"Zirngibl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet S M","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E","family":"Aubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Journal of Molecular Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/jme.bioscientifica.com\/view\/journals\/jme\/40\/2\/61.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/40\/2\/61.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:51:52Z","timestamp":1784555512000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/jme\/article\/40\/2\/61-73\/25017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,11,23]]},"references-count":0,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.1677\/jme-07-0114","relation":{},"ISSN":["0952-5041","1479-6813"],"issn-type":[{"value":"0952-5041","type":"print"},{"value":"1479-6813","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,11,23]]}}}