Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation
Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteobl...
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| Veröffentlicht in: | Cell metabolism 2010-02, Vol.11 (2), p.161-171 |
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| creator | Guo, Jun Liu, Minlin Yang, Dehong Bouxsein, Mary L. Saito, Hiroaki Galvin, R.J. Sells Kuhstoss, Stuart A. Thomas, Clare C. Schipani, Ernestina Baron, Roland Bringhurst, F. Richard Kronenberg, Henry M. |
| description | Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low-calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response (“osteitis fibrosis”) and new bone formation seen in wild-type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of β-catenin, and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1.
► PTH suppresses Dkk1 expression in osteoblasts ► PTH can activate Wnt signaling even in the presence of overexpressed Dkk1 ► Dkk overexpression in vivo blocks PTH action and new bone formation ► The full actions of PTH on bone require intact canonical Wnt signaling |
| doi_str_mv | 10.1016/j.cmet.2009.12.007 |
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► PTH suppresses Dkk1 expression in osteoblasts ► PTH can activate Wnt signaling even in the presence of overexpressed Dkk1 ► Dkk overexpression in vivo blocks PTH action and new bone formation ► The full actions of PTH on bone require intact canonical Wnt signaling</description><identifier>ISSN: 1550-4131</identifier><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2009.12.007</identifier><identifier>PMID: 20142103</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bone Marrow Cells - metabolism ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Gene Expression Regulation ; Humans ; HUMDISEASE ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Mice ; Mice, Inbred C57BL ; Osteoblasts - metabolism ; Osteoclasts - metabolism ; Osteogenesis ; Parathyroid Hormone - metabolism ; RNA, Messenger - genetics ; Signal Transduction ; Stromal Cells - metabolism ; Wnt Proteins - metabolism</subject><ispartof>Cell metabolism, 2010-02, Vol.11 (2), p.161-171</ispartof><rights>2010 Elsevier Inc.</rights><rights>Copyright 2010 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-54c262d774b5a14f46cb9efccdd294f76a4d0c7c3e2134e590470522521113b63</citedby><cites>FETCH-LOGICAL-c454t-54c262d774b5a14f46cb9efccdd294f76a4d0c7c3e2134e590470522521113b63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1550413109004057$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20142103$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Liu, Minlin</creatorcontrib><creatorcontrib>Yang, Dehong</creatorcontrib><creatorcontrib>Bouxsein, Mary L.</creatorcontrib><creatorcontrib>Saito, Hiroaki</creatorcontrib><creatorcontrib>Galvin, R.J. Sells</creatorcontrib><creatorcontrib>Kuhstoss, Stuart A.</creatorcontrib><creatorcontrib>Thomas, Clare C.</creatorcontrib><creatorcontrib>Schipani, Ernestina</creatorcontrib><creatorcontrib>Baron, Roland</creatorcontrib><creatorcontrib>Bringhurst, F. Richard</creatorcontrib><creatorcontrib>Kronenberg, Henry M.</creatorcontrib><title>Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation</title><title>Cell metabolism</title><addtitle>Cell Metab</addtitle><description>Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low-calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response (“osteitis fibrosis”) and new bone formation seen in wild-type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of β-catenin, and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1.
► PTH suppresses Dkk1 expression in osteoblasts ► PTH can activate Wnt signaling even in the presence of overexpressed Dkk1 ► Dkk overexpression in vivo blocks PTH action and new bone formation ► The full actions of PTH on bone require intact canonical Wnt signaling</description><subject>Animals</subject><subject>Bone Marrow Cells - metabolism</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>HUMDISEASE</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Osteoblasts - metabolism</subject><subject>Osteoclasts - metabolism</subject><subject>Osteogenesis</subject><subject>Parathyroid Hormone - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>Signal Transduction</subject><subject>Stromal Cells - metabolism</subject><subject>Wnt Proteins - metabolism</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1DAURiMEoqXwB1gg71gl-JW4lhBSO9AWqTzEFLG0HPtm8DSxg-206r_HoykVbFjZlr97rn1PVb0kuCGYdG-2jZkgNxRj2RDaYCweVYdEMloLTvHjsm9bXHPCyEH1LKUtxqxjkj2tDigmnBLMDiu3XuY5QkoueBQG9MNntHYbr0fnN6i_Q--vrwk6yRn8ojMk9PXqov4E1pWDRescw6RHtIJxRN8gzcEnQNpb9Blu0WnwgM5CnHQu9OfVk0GPCV7cr0fV97MPV6uL-vLL-cfVyWVteMtz3XJDO2qF4H2rCR94Z3oJgzHWUskH0WlusRGGASWMQysxF7iltKWEENZ37Kh6t-fOSz-BNeBz1KOao5t0vFNBO_XvjXc_1SbcKHpMpDymBfD6HhDDrwVSVpNLpvxQewhLUoIxSTshZEnSfdLEkFKE4aELwWqnSG3VTpHaKVKEqqKoFL36-30PJX-clMDbfQDKlG4cRJWMA2_K0COYrGxw_-P_Bs2_ov4</recordid><startdate>20100203</startdate><enddate>20100203</enddate><creator>Guo, Jun</creator><creator>Liu, Minlin</creator><creator>Yang, Dehong</creator><creator>Bouxsein, Mary L.</creator><creator>Saito, Hiroaki</creator><creator>Galvin, R.J. Sells</creator><creator>Kuhstoss, Stuart A.</creator><creator>Thomas, Clare C.</creator><creator>Schipani, Ernestina</creator><creator>Baron, Roland</creator><creator>Bringhurst, F. Richard</creator><creator>Kronenberg, Henry M.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100203</creationdate><title>Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation</title><author>Guo, Jun ; Liu, Minlin ; Yang, Dehong ; Bouxsein, Mary L. ; Saito, Hiroaki ; Galvin, R.J. Sells ; Kuhstoss, Stuart A. ; Thomas, Clare C. ; Schipani, Ernestina ; Baron, Roland ; Bringhurst, F. Richard ; Kronenberg, Henry M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-54c262d774b5a14f46cb9efccdd294f76a4d0c7c3e2134e590470522521113b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Bone Marrow Cells - metabolism</topic><topic>Cell Line</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>HUMDISEASE</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Osteoblasts - metabolism</topic><topic>Osteoclasts - metabolism</topic><topic>Osteogenesis</topic><topic>Parathyroid Hormone - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>Signal Transduction</topic><topic>Stromal Cells - metabolism</topic><topic>Wnt Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Liu, Minlin</creatorcontrib><creatorcontrib>Yang, Dehong</creatorcontrib><creatorcontrib>Bouxsein, Mary L.</creatorcontrib><creatorcontrib>Saito, Hiroaki</creatorcontrib><creatorcontrib>Galvin, R.J. 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Richard</creatorcontrib><creatorcontrib>Kronenberg, Henry M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guo, Jun</au><au>Liu, Minlin</au><au>Yang, Dehong</au><au>Bouxsein, Mary L.</au><au>Saito, Hiroaki</au><au>Galvin, R.J. Sells</au><au>Kuhstoss, Stuart A.</au><au>Thomas, Clare C.</au><au>Schipani, Ernestina</au><au>Baron, Roland</au><au>Bringhurst, F. Richard</au><au>Kronenberg, Henry M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2010-02-03</date><risdate>2010</risdate><volume>11</volume><issue>2</issue><spage>161</spage><epage>171</epage><pages>161-171</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><abstract>Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low-calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response (“osteitis fibrosis”) and new bone formation seen in wild-type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of β-catenin, and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1.
► PTH suppresses Dkk1 expression in osteoblasts ► PTH can activate Wnt signaling even in the presence of overexpressed Dkk1 ► Dkk overexpression in vivo blocks PTH action and new bone formation ► The full actions of PTH on bone require intact canonical Wnt signaling</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20142103</pmid><doi>10.1016/j.cmet.2009.12.007</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Bone Marrow Cells - metabolism Cell Line Cell Proliferation Cells, Cultured Gene Expression Regulation Humans HUMDISEASE Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Mice Mice, Inbred C57BL Osteoblasts - metabolism Osteoclasts - metabolism Osteogenesis Parathyroid Hormone - metabolism RNA, Messenger - genetics Signal Transduction Stromal Cells - metabolism Wnt Proteins - metabolism |
| title | Suppression of Wnt Signaling by Dkk1 Attenuates PTH-Mediated Stromal Cell Response and New Bone Formation |
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