Skip to main content
Erschienen in: Calcified Tissue International 6/2009

01.12.2009

Biphasic Glucocorticoid-Dependent Regulation of Wnt Expression and Its Inhibitors in Mature Osteoblastic Cells

verfasst von: Wendy Mak, Xinyu Shao, Colin R. Dunstan, Markus J. Seibel, Hong Zhou

Erschienen in: Calcified Tissue International | Ausgabe 6/2009

Einloggen, um Zugang zu erhalten

Abstract

Glucocorticoids exert both anabolic and catabolic effects on bone. Previously, we reported that endogenous glucocorticoids control mesenchymal lineage commitment and osteoblastogenesis through regulation of Wnt signaling in osteoblasts. Here, we investigated the effects of glucocorticoids on Wnt expression in mature osteoblasts. Mature osteoblasts and their immature progenitors were separately isolated from Col2.3-GFP transgenic mice in which mature osteoblasts are identifiable through GFP expression. mRNA levels of Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt10b, and Wnt11 were 4- to 12-fold higher in osteoblasts compared to their progenitors (P < 0.05). Expression of Wnt7b and Wnt10b in osteoblasts was modulated by corticosterone (CS), in a biphasic fashion with 3- to 3.5-fold upregulation at 10 nM CS (P < 0.01) and 50% downregulation at 100 nM CS (P < 0.05). CS 100 nM also increased expression of the Wnt inhibitors sFRP-1 and DKK-1 two- to threefold (P < 0.05). We conclude that the contrasting anabolic and catabolic effects of glucocorticoids on bone are, at least in part, mediated through the regulation of Wnt expression and its inhibitors in mature osteoblasts.
Literatur
1.
Zurück zum Zitat Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521CrossRefPubMed Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521CrossRefPubMed
2.
Zurück zum Zitat Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA II, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314CrossRefPubMed Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA II, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314CrossRefPubMed
3.
Zurück zum Zitat Li X, Liu P, Liu W, Maye P, Zhang J, Zhang Y, Hurley M, Guo C, Boskey A, Sun L, Harris SE, Rowe DW, Ke HZ, Wu D (2005) Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37:945–952CrossRefPubMed Li X, Liu P, Liu W, Maye P, Zhang J, Zhang Y, Hurley M, Guo C, Boskey A, Sun L, Harris SE, Rowe DW, Ke HZ, Wu D (2005) Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 37:945–952CrossRefPubMed
4.
Zurück zum Zitat Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887CrossRefPubMed Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887CrossRefPubMed
5.
Zurück zum Zitat Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998–31004CrossRefPubMed Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998–31004CrossRefPubMed
6.
Zurück zum Zitat Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC (2006) CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955–2964CrossRefPubMed Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC (2006) CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955–2964CrossRefPubMed
7.
Zurück zum Zitat Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750CrossRefPubMed Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750CrossRefPubMed
8.
Zurück zum Zitat Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738CrossRefPubMed Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738CrossRefPubMed
9.
Zurück zum Zitat Zhou H, Mak W, Kalak R, Street J, Fong-Yee C, Zheng Y, Dunstan CR, Seibel MJ (2009) Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice. Development 136:427–436CrossRefPubMed Zhou H, Mak W, Kalak R, Street J, Fong-Yee C, Zheng Y, Dunstan CR, Seibel MJ (2009) Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice. Development 136:427–436CrossRefPubMed
10.
Zurück zum Zitat Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, Macdougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329CrossRefPubMed Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, Macdougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329CrossRefPubMed
11.
Zurück zum Zitat Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60CrossRefPubMed Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49–60CrossRefPubMed
12.
Zurück zum Zitat Zhou H, Mak W, Zheng Y, Dunstan CR, Seibel MJ (2008) Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem 283:1936–1945CrossRefPubMed Zhou H, Mak W, Zheng Y, Dunstan CR, Seibel MJ (2008) Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem 283:1936–1945CrossRefPubMed
13.
14.
Zurück zum Zitat Woitge H, Harrison J, Ivkosic A, Krozowski Z, Kream B (2001) Cloning and in vitro characterization of alpha 1(I)-collagen 11beta-hydroxysteroid dehydrogenase type 2 transgenes as models for osteoblast-selective inactivation of natural glucocorticoids. Endocrinology 142:1341–1348CrossRefPubMed Woitge H, Harrison J, Ivkosic A, Krozowski Z, Kream B (2001) Cloning and in vitro characterization of alpha 1(I)-collagen 11beta-hydroxysteroid dehydrogenase type 2 transgenes as models for osteoblast-selective inactivation of natural glucocorticoids. Endocrinology 142:1341–1348CrossRefPubMed
15.
Zurück zum Zitat Sher LB, Woitge HW, Adams DJ, Gronowicz GA, Krozowski Z, Harrison JR, Kream BE (2004) Transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2 in osteoblasts reveals an anabolic role for endogenous glucocorticoids in bone. Endocrinology 145:922–929CrossRefPubMed Sher LB, Woitge HW, Adams DJ, Gronowicz GA, Krozowski Z, Harrison JR, Kream BE (2004) Transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2 in osteoblasts reveals an anabolic role for endogenous glucocorticoids in bone. Endocrinology 145:922–929CrossRefPubMed
16.
Zurück zum Zitat Kalajzic I, Kalajzic Z, Kaliterna M, Gronowicz G, Clark SH, Lichtler AC, Rowe D (2002) Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J Bone Miner Res 17:15–25CrossRefPubMed Kalajzic I, Kalajzic Z, Kaliterna M, Gronowicz G, Clark SH, Lichtler AC, Rowe D (2002) Use of type I collagen green fluorescent protein transgenes to identify subpopulations of cells at different stages of the osteoblast lineage. J Bone Miner Res 17:15–25CrossRefPubMed
17.
Zurück zum Zitat Kalajzic Z, Liu P, Kalajzic I, Du Z, Braut A, Mina M, Canalis E, Rowe DW (2002) Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters. Bone 31:654–660CrossRefPubMed Kalajzic Z, Liu P, Kalajzic I, Du Z, Braut A, Mina M, Canalis E, Rowe DW (2002) Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters. Bone 31:654–660CrossRefPubMed
18.
Zurück zum Zitat Shi YC, Worton L, Esteban L, Baldock P, Fong C, Eisman JA, Gardiner EM (2007) Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. Bone 41:87–96CrossRefPubMed Shi YC, Worton L, Esteban L, Baldock P, Fong C, Eisman JA, Gardiner EM (2007) Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. Bone 41:87–96CrossRefPubMed
19.
Zurück zum Zitat Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939–27944CrossRefPubMed Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939–27944CrossRefPubMed
20.
Zurück zum Zitat Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810CrossRefPubMed Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810CrossRefPubMed
21.
Zurück zum Zitat Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S (2005) Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem 280:41342–41351CrossRefPubMed Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S (2005) Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem 280:41342–41351CrossRefPubMed
22.
Zurück zum Zitat Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L, Hole N (2001) Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing haematopoietic differentiation. Mech Dev 103:49–59CrossRefPubMed Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L, Hole N (2001) Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing haematopoietic differentiation. Mech Dev 103:49–59CrossRefPubMed
23.
Zurück zum Zitat Wang H, Gilner JB, Bautch VL, Wang DZ, Wainwright BJ, Kirby SL, Patterson C (2007) Wnt2 coordinates the commitment of mesoderm to hematopoietic, endothelial, and cardiac lineages in embryoid bodies. J Biol Chem 282:782–791CrossRefPubMed Wang H, Gilner JB, Bautch VL, Wang DZ, Wainwright BJ, Kirby SL, Patterson C (2007) Wnt2 coordinates the commitment of mesoderm to hematopoietic, endothelial, and cardiac lineages in embryoid bodies. J Biol Chem 282:782–791CrossRefPubMed
24.
Zurück zum Zitat Engelbrecht Y, de Wet H, Horsch K, Langeveldt CR, Hough FS, Hulley PA (2003) Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. Endocrinology 144:412–422CrossRefPubMed Engelbrecht Y, de Wet H, Horsch K, Langeveldt CR, Hough FS, Hulley PA (2003) Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. Endocrinology 144:412–422CrossRefPubMed
25.
Zurück zum Zitat Rickard DJ, Sullivan TA, Shenker BJ, Leboy PS, Kazhdan I (1994) Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev Biol 161:218–228CrossRefPubMed Rickard DJ, Sullivan TA, Shenker BJ, Leboy PS, Kazhdan I (1994) Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev Biol 161:218–228CrossRefPubMed
26.
Zurück zum Zitat Scutt A, Bertram P (1999) Basic fibroblast growth factor in the presence of dexamethasone stimulates colony formation, expansion, and osteoblastic differentiation by rat bone marrow stromal cells. Calcif Tissue Int 64:69–77CrossRefPubMed Scutt A, Bertram P (1999) Basic fibroblast growth factor in the presence of dexamethasone stimulates colony formation, expansion, and osteoblastic differentiation by rat bone marrow stromal cells. Calcif Tissue Int 64:69–77CrossRefPubMed
27.
Zurück zum Zitat Smith E, Frenkel B (2005) Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3beta-dependent and -independent manner. J Biol Chem 280:2388–2394CrossRefPubMed Smith E, Frenkel B (2005) Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3beta-dependent and -independent manner. J Biol Chem 280:2388–2394CrossRefPubMed
28.
Zurück zum Zitat Walsh S, Jordan GR, Jefferiss C, Stewart K, Beresford JN (2001) High concentrations of dexamethasone suppress the proliferation but not the differentiation or further maturation of human osteoblast precursors in vitro: relevance to glucocorticoid-induced osteoporosis. Rheumatology (Oxford) 40:74–83CrossRef Walsh S, Jordan GR, Jefferiss C, Stewart K, Beresford JN (2001) High concentrations of dexamethasone suppress the proliferation but not the differentiation or further maturation of human osteoblast precursors in vitro: relevance to glucocorticoid-induced osteoporosis. Rheumatology (Oxford) 40:74–83CrossRef
29.
Zurück zum Zitat Kalak R, Zhou H, Street J, Day R, Modzelewski J, Liu P, Li G, Dunstan C, Seibel MJ (2009) Endogenous glucocorticoid signaling in osteoblasts is necessary to maintain normal bone structure in mice. Bone 45:61–67CrossRefPubMed Kalak R, Zhou H, Street J, Day R, Modzelewski J, Liu P, Li G, Dunstan C, Seibel MJ (2009) Endogenous glucocorticoid signaling in osteoblasts is necessary to maintain normal bone structure in mice. Bone 45:61–67CrossRefPubMed
30.
Zurück zum Zitat Sher LB, Harrison JR, Adams DJ, Kream BE (2006) Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-targeted disruption of glucocorticoid signaling. Calcif Tissue Int 79:118–125CrossRefPubMed Sher LB, Harrison JR, Adams DJ, Kream BE (2006) Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-targeted disruption of glucocorticoid signaling. Calcif Tissue Int 79:118–125CrossRefPubMed
31.
Zurück zum Zitat Ishida Y, Heersche JN (1998) Glucocorticoid-induced osteoporosis: both in vivo and in vitro concentrations of glucocorticoids higher than physiological levels attenuate osteoblast differentiation. J Bone Miner Res 13:1822–1826CrossRefPubMed Ishida Y, Heersche JN (1998) Glucocorticoid-induced osteoporosis: both in vivo and in vitro concentrations of glucocorticoids higher than physiological levels attenuate osteoblast differentiation. J Bone Miner Res 13:1822–1826CrossRefPubMed
32.
Zurück zum Zitat O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841CrossRefPubMed O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841CrossRefPubMed
Metadaten
Titel
Biphasic Glucocorticoid-Dependent Regulation of Wnt Expression and Its Inhibitors in Mature Osteoblastic Cells
verfasst von
Wendy Mak
Xinyu Shao
Colin R. Dunstan
Markus J. Seibel
Hong Zhou
Publikationsdatum
01.12.2009
Verlag
Springer-Verlag
Erschienen in
Calcified Tissue International / Ausgabe 6/2009
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-009-9303-1

Weitere Artikel der Ausgabe 6/2009

Calcified Tissue International 6/2009 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Reizdarmsyndrom: Diäten wirksamer als Medikamente

29.04.2024 Reizdarmsyndrom Nachrichten

Bei Reizdarmsyndrom scheinen Diäten, wie etwa die FODMAP-arme oder die kohlenhydratreduzierte Ernährung, effektiver als eine medikamentöse Therapie zu sein. Das hat eine Studie aus Schweden ergeben, die die drei Therapieoptionen im direkten Vergleich analysierte.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.