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J. Biol. Chem., Vol. 278, Issue 27, 24377-24387, July 4, 2003

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Gap Junctional Communication Modulates Gene Transcription by Altering the Recruitment of Sp1 and Sp3 to Connexin-response Elements in Osteoblast Promoters^*

Joseph P. Stains , Fernando Lecanda  ¶, Joanne Screen , Dwight A. Towler  and Roberto Civitelli  ||

From the Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri 63110 and the Department of Histology and Pathology, University of Navarra, Pamplona 31080, Spain

Loss-of-function mutations of gap junction proteins, connexins, represent a mechanism of disease in a variety of tissues. We have shown that recessive (gene deletion) or dominant (connexin45 overexpression) disruption of connexin43 function results in osteoblast dysfunction and abnormal expression of osteoblast genes, including down-regulation of osteocalcin transcription. To elucidate the molecular mechanisms of gap junction-sensitive transcriptional regulation, we systematically analyzed the rat osteocalcin promoter for sensitivity to gap junctional intercellular communication. We identified an Sp1/Sp3 containing complex that assembles on a minimal element in the –70 to –57 region of the osteocalcin promoter in a gap junction-dependent manner. This CT-rich connexin-response element is necessary and sufficient to confer gap junction sensitivity to the osteocalcin proximal promoter. Repression of osteocalcin transcription occurs as a result of displacement of the stimulatory Sp1 by the inhibitory Sp3 on the promoter when gap junctional communication is perturbed. Modulation of Sp1/Sp3 recruitment also occurs on the collagen I1 promoter and translates into gap junction-sensitive transcriptional control of collagen I1 gene expression. Thus, regulation of Sp1/Sp3 recruitment to the promoter may represent a potential general mechanism for transcriptional control of target genes by signals passing through gap junctions.

Received for publication, December 9, 2002 , and in revised form, March 13, 2003.

^* This work was supported in part by NIAMS Grants R01 AR41255 (to R. C.) and T32 AR07033 (to J. S.) from the National Institutes of Health, in part by National Aeronautics and Space Administration Grant NRA 99-HEDS-02-110, and by funds from the Barnes-Jewish Hospital Foundation, St. Louis, MO. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Fellow from Ramón y Cajal Program and supported by funds from the Ministry of Science and Technology (I+D) and Government of Navarra (Ortiz de Landázuri Scholarship), Spain.

^|| To whom correspondence should be addressed: Division of Bone and Mineral Diseases, Dept. of Internal Medicine, Barnes-Jewish Hospital, North Campus, 216 S. Kingshighway Blvd., St. Louis, MO 63110. Tel.: 314-454-7765; Fax: 314-454-5047; E-mail: rcivitel{at}im.wustl.edu.

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