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Endocrine
Published in: Endocrine 3/2012

Open Access 01-12-2012 | Original Article

Cyclic AMP signaling in bone marrow stromal cells has reciprocal effects on the ability of mesenchymal stem cells to differentiate into mature osteoblasts versus mature adipocytes

Authors: Richard Kao, Weidar Lu, Alyssa Louie, Robert Nissenson

Published in: Endocrine | Issue 3/2012

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Abstract

Stimulatory G protein-mediated cAMP signaling is intimately involved in skeletal homeostasis. However, limited information is available on the role of the cAMP signaling in regulating the differentiation of mesenchymal stem cells into mature osteoblasts and adipocytes. To investigate this, we treated primary mouse bone marrow stromal cells (BMSCs) with forskolin to stimulate cAMP signaling and determined the effect on osteoblast and adipocyte differentiation. Exposure of differentiating osteoblasts to forskolin markedly inhibited progression to the late stages of osteoblast differentiation, and this effect was replicated by continuous exposure to PTH. Strikingly, forskolin activation of cAMP signaling in BMSCs conditioned mesenchymal stem cells (MSCs) to undergo increased osteogenic differentiation and decreased adipogenic differentiation. PTH treatment of BMSCs also enhanced subsequent osteogenesis, but promoted an increased adipogenesis as well. Thus, activation of cAMP signaling alters the lineage commitment of MSCs, favoring osteogenesis at the expense of adipogenesis.
Literature
1.
L.S. Weinstein et al., Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N. Engl. J. Med. 325(24), 1688–1695 (1991)PubMedCrossRef
2.
W.F. Schwindinger, C.A. Francomano, M.A. Levine, Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune–Albright syndrome. Proc. Natl. Acad. Sci. USA 89(11), 5152–5156 (1992)PubMedCrossRef
3.
A. Shenker et al., Severe endocrine and nonendocrine manifestations of the McCune–Albright syndrome associated with activating mutations of stimulatory G protein GS. J. Pediatr. 123(4), 509–518 (1993)PubMedCrossRef
4.
C.D. Malchoff et al., An unusual presentation of McCune–Albright syndrome confirmed by an activating mutation of the Gs alpha-subunit from a bone lesion. J. Clin. Endocrinol. Metab. 78(3), 803–806 (1994)PubMedCrossRef
5.
A. Shenker et al., An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune–Albright syndrome. J. Clin. Endocrinol. Metab. 79(3), 750–755 (1994)PubMedCrossRef
6.
P.J. Marie et al., Increased proliferation of osteoblastic cells expressing the activating Gs alpha mutation in monostotic and polyostotic fibrous dysplasia. Am. J. Pathol. 150(3), 1059–1069 (1997)PubMed
7.
B.A. Alman, D.A. Greel, H.J. Wolfe, Activating mutations of Gs protein in monostotic fibrous lesions of bone. J. Orthop. Res. 14(2), 311–315 (1996)PubMedCrossRef
8.
M. Riminucci et al., Fibrous dysplasia of bone in the McCune–Albright syndrome: abnormalities in bone formation. Am. J. Pathol. 151(6), 1587–1600 (1997)PubMed
9.
S. Piersanti et al., Transfer, analysis, and reversion of the fibrous dysplasia cellular phenotype in human skeletal progenitors. J. Bone Miner. Res. 25(5), 1103–1116 (2010)PubMed
10.
A. Sakamoto et al., Deficiency of the G-protein alpha-subunit G(s)alpha in osteoblasts leads to differential effects on trabecular and cortical bone. J. Biol. Chem. 280(22), 21369–21375 (2005)PubMedCrossRef
11.
E.C. Hsiao et al., Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass. Proc. Natl. Acad. Sci. USA 105(4), 1209–1214 (2008)PubMedCrossRef
12.
L.M. Calvi et al., Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J. Clin. Invest. 107(3), 277–286 (2001)PubMedCrossRef
13.
J. Peng et al., Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia. Endocrinology 149(3), 1329–1337 (2007)PubMedCrossRef
14.
R.C. Gensure, T.J. Gardella, H. Juppner, Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem. Biophys. Res. Commun. 328(3), 666–678 (2005)PubMedCrossRef
15.
H. Juppner et al., A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254(5034), 1024–1026 (1991)PubMedCrossRef
16.
W.F. Schwindinger et al., Coupling of the PTH/PTHrP receptor to multiple G-proteins. Direct demonstration of receptor activation of Gs, Gq/11, and Gi(1) by [alpha-32P]GTP-gamma-azidoanilide photoaffinity labeling. Endocrine 8(2), 201–209 (1998)PubMedCrossRef
17.
C. Ge et al., Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell Biol. 176(5), 709–718 (2007)PubMedCrossRef
18.
A. Rey et al., Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation. J. Biol. Chem. 281(50), 38181–38188 (2006)PubMedCrossRef
19.
R. Armamento-Villareal et al., An intact N terminus is required for the anabolic action of parathyroid hormone on adult female rats. J. Bone Miner. Res. 12(3), 384–392 (1997)PubMedCrossRef
20.
S. Hilliker et al., Truncation of the amino terminus of PTH alters its anabolic activity on bone in vivo. Bone 19(5), 469–477 (1996)PubMedCrossRef
21.
R.H. Rixon et al., Parathyroid hormone fragments may stimulate bone growth in ovariectomized rats by activating adenylyl cyclase. J. Bone Miner. Res. 9(8), 1179–1189 (1994)PubMedCrossRef
22.
J.F. Whitfield et al., Stimulation of the growth of femoral trabecular bone in ovariectomized rats by the novel parathyroid hormone fragment, hPTH-(1-31)NH2 (Ostabolin). Calcif. Tissue Int. 58(2), 81–87 (1996)PubMedCrossRef
23.
A. Hollnagel, M. Ahrens, G. Gross, Parathyroid hormone enhances early and suppresses late stages of osteogenic and chondrogenic development in a BMP-dependent mesenchymal differentiation system (C3H10T1/2). J. Bone Miner. Res. 12(12), 1993–2004 (1997)PubMedCrossRef
24.
T. Akune et al., PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113(6), 846–855 (2004)PubMed
25.
R.F. Klein et al., Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303(5655), 229–232 (2004)PubMedCrossRef
26.
D.J. Rickard et al., Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells. Bone 39(6), 1361–1372 (2006)PubMedCrossRef
27.
Y. Tintut et al., cAMP stimulates osteoblast-like differentiation of calcifying vascular cells. Potential signaling pathway for vascular calcification. J. Biol. Chem. 273(13), 7547–7553 (1998)PubMedCrossRef
28.
R. Siddappa et al., cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc. Natl. Acad. Sci. USA 105(20), 7281–7286 (2008)PubMedCrossRef
29.
J. Doorn et al., Forskolin enhances in vivo bone formation by human mesenchymal stromal cells. Tissue Eng. Part A 18(5–6), 558–567 (2012)PubMedCrossRef
30.
A. Scutt, N. Beier, C. Fittschen, EMD273316 & EMD95833, type 4 phosphodiesterase inhibitors, stimulate fibroblastic-colony formation by bone marrow cells via direct inhibition of PDE4 and the induction of endogenous prostaglandin synthesis. BMC Pharmacol. 4, 10 (2004)PubMedCrossRef
31.
Y. Zhao, S. Ding, A high-throughput siRNA library screen identifies osteogenic suppressors in human mesenchymal stem cells. Proc. Natl. Acad. Sci. USA 104(23), 9673–9678 (2007)PubMedCrossRef
32.
D.C. Yang et al., cAMP/PKA regulates osteogenesis, adipogenesis and ratio of RANKL/OPG mRNA expression in mesenchymal stem cells by suppressing leptin. PLoS One 3(2), e1540 (2008)PubMedCrossRef
33.
R. Siddappa et al., cAMP/PKA signaling inhibits osteogenic differentiation and bone formation in rodent models. Tissue Eng. Part A 15(8), 2135–2143 (2009)PubMedCrossRef
34.
Y. Gong et al., LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107(4), 513–523 (2001)PubMedCrossRef
35.
L.M. Boyden et al., High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346(20), 1513–1521 (2002)PubMedCrossRef
36.
R.D. Little et al., A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70(1), 11–19 (2002)PubMedCrossRef
37.
T.F. Day et al., Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8(5), 739–750 (2005)PubMedCrossRef
38.
T. Gaur et al., Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280(39), 33132–33140 (2005)PubMedCrossRef
39.
R.A. Terkeltaub, Inorganic pyrophosphate generation and disposition in pathophysiology. Am. J. Physiol. Cell Physiol. 281(1), C1–C11 (2001)PubMed
40.
A. Baba et al., PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. Nat. Cell Biol. 13(6), 668–675 (2011)PubMedCrossRef
41.
J. Guo et al., Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell. Metab. 11(2), 161–171 (2010)PubMedCrossRef
42.
C. O’Brien et al., Activation of PTH receptor 1 specifically in osteocytes suppresses Sost expression and increases bone mass in transgenic mice. J. Bone Miner. Res. 20, S4 (2006)
43.
N.H. Kulkarni et al., Effects of parathyroid hormone on Wnt signaling pathway in bone. J. Cell. Biochem. 95(6), 1178–1190 (2005)PubMedCrossRef
44.
G. Liu et al., Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. J. Cell Biol. 185(1), 67–75 (2009)PubMedCrossRef
45.
N. Quarto, B. Behr, M.T. Longaker, Opposite spectrum of activity of canonical Wnt signaling in the osteogenic context of undifferentiated and differentiated mesenchymal cells: implications for tissue engineering. Tissue Eng. Part A 16(10), 3185–3197 (2010)PubMedCrossRef
46.
G.M. Boland et al., Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J. Cell. Biochem. 93(6), 1210–1230 (2004)PubMedCrossRef
47.
H. Zhou et al., Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J. Biol. Chem. 283(4), 1936–1945 (2008)PubMedCrossRef
48.
M. Terauchi et al., T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 10(3), 229–240 (2009)PubMedCrossRef
49.
P.H. Luiz de Freitas et al., Intermittent PTH administration stimulates pre-osteoblastic proliferation without leading to enhanced bone formation in osteoclast-less c-fos(−/−) mice. J. Bone Miner. Res. 24(9), 1586–1597 (2009)PubMedCrossRef
50.
S.A. Kuznetsov et al., The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J. Cell Biol. 167(6), 1113–1122 (2004)PubMedCrossRef
51.
M. Katebi, M. Soleimani, B.N. Cronstein, Adenosine A2A receptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. J. Leukoc. Biol. 85(3), 438–444 (2009)PubMedCrossRef
52.
S.H. Carroll et al., The A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J. Biol. Chem. 287(19), 15718–15727 (2012)PubMedCrossRef
53.
B. Gharibi et al., Contrasting effects of A1 and A2b adenosine receptors on adipogenesis. Int. J. Obes. (Lond.) 36(3), 397–406 (2012)CrossRef
Metadata
Title
Cyclic AMP signaling in bone marrow stromal cells has reciprocal effects on the ability of mesenchymal stem cells to differentiate into mature osteoblasts versus mature adipocytes
Authors
Richard Kao
Weidar Lu
Alyssa Louie
Robert Nissenson
Publication date
01-12-2012
Publisher
Springer US
Published in
Endocrine / Issue 3/2012
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-012-9717-9

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