Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ (PPARγ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPARγ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine. 1. Introduction Mesenchymal stem cells (MSC) are multipotent stromal cells capable of self-renewal and capable of multilineage mesenchymal differentiation [1]. These nonhematopoietic cells can differentiate down multiple mesenchymal lineages, including osteogenic, chondrogenic, adipogenic, myogenic, and neurogenic lineages [2] (Figure 1). Originally identified in the bone marrow, MSC are readily obtained from numerous mesenchymal tissue types, including skeletal muscle and adipose depots. In particular, adipose tissue is an attractive source for MSC isolation, as it is readily accessible with minimal morbidity by routine liposuction procedures [3–5]. Indeed, human adipose-derived stromal cells (or hASC) have been demonstrated to have significant potential for use in tissue engineering applications, as shown in preclinical animal models [6]. However, the uncultured stromal vascular fraction of adipose tissue represents a heterogeneous cell population that is not
References
[1]
W. M. Jackson, L. J. Nesti, and R. S. Tuan, “Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells,” Stem Cells Translational Medicine, vol. 1, no. 1, pp. 44–50, 2012.
[2]
G. Chamberlain, J. Fox, B. Ashton, and J. Middleton, “Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing,” Stem Cells, vol. 25, no. 11, pp. 2739–2749, 2007.
[3]
B. Levi and M. T. Longaker, “Concise review: adipose-derived stromal cells for skeletal regenerative medicine,” Stem Cells, vol. 29, no. 4, pp. 576–582, 2011.
[4]
H. Mizuno, M. Tobita, and A. C. Uysal, “Concise review: adipose-derived stem cells as a novel tool for future regenerative medicine,” Stem Cells, vol. 30, no. 5, pp. 804–810, 2012.
[5]
A. W. James, J. N. Zara, X. Zhang, et al., “Perivascular stem cells: a prospectively purified mesenchymal stem cell population for bone tissue engineering,” Stem Cells Translational Medicine, vol. 1, no. 6, pp. 510–519, 2012.
[6]
B. Levi, A. W. James, E. R. Nelson et al., “Human adipose derived stromal cells heal critical size mouse calvarial defects,” PLoS ONE, vol. 5, no. 6, Article ID e11177, 2010.
[7]
B. Levi, D. C. Wan, J. P. Glotzbach et al., “CD105 protein depletion enhances human adipose-derived stromal cell osteogenesis through reduction of transforming growth factor β1 (TGF-β1) signaling,” The Journal of Biological Chemistry, vol. 286, no. 45, pp. 39497–39509, 2011.
[8]
D. W. Kim, M. Staples, K. Shinozuka, et al., “Wharton's Jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications,” International Journal of Molecular Sciences, vol. 14, no. 6, pp. 11692–11712, 2013.
[9]
S. Corrao, G. la Rocca, M. Lo Iacono, T. Corsello, F. Farina, and R. Anzalone, “Umbilical cord revisited: from Wharton's jelly myofibroblasts to mesenchymal stem cells,” Histology and Histopathology, vol. 28, no. 10, pp. 1235–1244, 2013.
[10]
M. Corselli, M. Crisan, I. R. Murray, et al., “Identification of perivascular mesenchymal stromal/stem cells by flow cytometry,” Cytometry A, vol. 83, no. 8, pp. 714–720, 2013.
[11]
A. W. James, J. N. Zarab, M. Corselli, et al., “An abundant perivascular source of stem cells for bone tissue engineering,” Stem Cells Translational Medicine, vol. 1, no. 9, pp. 673–684, 2012.
[12]
M. Corselli, C. W. Chen, B. Sun, et al., “The tunica adventitia of human arteries and veins as a source of mesenchymal stem cells,” Stem Cells and Development, vol. 21, no. 8, pp. 1299–1308, 2012.
[13]
M. Crisan, S. Yap, L. Casteilla et al., “A perivascular origin for mesenchymal stem cells in multiple human organs,” Cell Stem Cell, vol. 3, no. 3, pp. 301–313, 2008.
[14]
J. Sammons, N. Ahmed, M. El-Sheemy, and H. T. Hassan, “The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D3,” Stem Cells and Development, vol. 13, no. 3, pp. 273–280, 2004.
[15]
A. Augello and C. De Bari, “The regulation of differentiation in mesenchymal stem cells,” Human Gene Therapy, vol. 21, no. 10, pp. 1226–1238, 2010.
[16]
D. J. Kelly and C. R. Jacobs, “The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells,” Birth Defects Research C, vol. 90, no. 1, pp. 75–85, 2010.
[17]
M. Hronik-Tupaj, W. L. Rice, M. Cronin-Golomb, D. L. Kaplan, and I. Georgakoudi, “Osteoblastic differentiation and stress response of human mesenchymal stem cells exposed to alternating current electric fields,” BioMedical Engineering Online, vol. 10, article 9, 2011.
[18]
C. M. Creecy, C. F. O'Neill, B. P. Arulanandam, V. L. Sylvia, C. S. Navara, and R. Bizios, “Mesenchymal stem cell osteodifferentiation in response to alternating electric current,” Tissue Engineering A, vol. 19, no. 3-4, pp. 467–474.
[19]
K. E. Hammerick, A. W. James, Z. Huang, F. B. Prinz, and M. T. Longaker, “Pulsed direct current electric fields enhance osteogenesis in adipose-derived stromal cells,” Tissue Engineering A, vol. 16, no. 3, pp. 917–931, 2010.
[20]
J. Yan, L. Dong, B. Zhang, and N. Qi, “Effects of extremely low-frequency magnetic field on growth and differentiation of human mesenchymal stem cells,” Electromagnetic Biology and Medicine, vol. 29, no. 4, pp. 165–176, 2010.
[21]
S. Muruganandan, A. A. Roman, and C. J. Sinal, “Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program,” Cellular and Molecular Life Sciences, vol. 66, no. 2, pp. 236–253, 2009.
[22]
E. D. Rosen and O. A. MacDougald, “Adipocyte differentiation from the inside out,” Nature Reviews Molecular Cell Biology, vol. 7, no. 12, pp. 885–896, 2006.
[23]
E. D. Rosen, C. J. Walkey, P. Puigserver, and B. M. Spiegelman, “Transcriptional regulation of adipogenesis,” Genes and Development, vol. 14, no. 11, pp. 1293–1307, 2000.
[24]
R. Berry and M. S. Rodeheffer, “Characterization of the adipocyte cellular lineage in vivo,” Nature Cell Biology, vol. 15, no. 3, pp. 302–308.
[25]
M. Jumabay, R. Abdmaulen, S. Urs, et al., “Endothelial differentiation in multipotent cells derived from mouse and human white mature adipocytes,” Journal of Molecular and Cellular Cardiology, vol. 53, no. 6, pp. 790–800, 2012.
[26]
I. O. Vroegrijk, J. B. van Klinken, J. A. van Diepen, et al., “Cd36 is important for adipocyte recruitment and affects lipolysis,” Obesity, 2013.
[27]
A. Neve, A. Corrado, and F. P. Cantatore, “Osteoblast physiology in normal and pathological conditions,” Cell and Tissue Research, vol. 343, no. 2, pp. 289–302, 2011.
[28]
K. Watanabe and K. Ikeda, “Osteoblast differentiation and bone formation,” Nippon Rinsho, vol. 67, no. 5, pp. 879–886, 2009.
[29]
A. W. James, S. Pang, A. Askarinam, M. Corselli, et al., “Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells,” Stem Cells and Development, vol. 21, no. 12, pp. 2170–2178.
[30]
L. Pei and P. Tontonoz, “Fat's loss is bone's gain,” Journal of Clinical Investigation, vol. 113, no. 6, pp. 805–806, 2004.
[31]
J. N. Beresford, J. H. Bennett, C. Devlin, P. S. Leboy, and M. E. Owen, “Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures,” Journal of Cell Science, vol. 102, no. 2, pp. 341–351, 1992.
[32]
M.-A. Dorheim, M. Sullivan, V. Dandapani et al., “Osteoblastic gene expression during adipogenesis in hematopoietic supporting murine bone marrow stromal cells,” Journal of Cellular Physiology, vol. 154, no. 2, pp. 317–328, 1993.
[33]
V. Krishnan, H. U. Bryant, and O. A. MacDougald, “Regulation of bone mass by Wnt signaling,” Journal of Clinical Investigation, vol. 116, no. 5, pp. 1202–1209, 2006.
[34]
C. N. Bennett, K. A. Longo, W. S. Wright et al., “Regulation of osteoblastogenesis and bone mass by Wnt10b,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 9, pp. 3324–3329, 2005.
[35]
Q.-Q. Tang, T. C. Otto, and M. D. Lane, “Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 26, pp. 9607–9611, 2004.
[36]
J. Burroughs, P. Gupta, B. R. Blazar, and C. M. Verfaillie, “Diffusible factors from the murine cell line M2-10B4 support human in vitro hematopoiesis,” Experimental Hematology, vol. 22, no. 11, pp. 1095–1101, 1994.
[37]
I. D'Alimonte, A. Lannutti, C. Pipino, et al., “Wnt signaling behaves as a “master regulator” in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells,” Stem Cell Reviews and Reports, vol. 9, no. 5, pp. 642–654, 2013.
[38]
H. Taipaleenm？ki, B. M. Abdallah, A. AlDahmash, A.-M. S？？m？nen, and M. Kassem, “Wnt signalling mediates the cross-talk between bone marrow derived pre-adipocytic and pre-osteoblastic cell populations,” Experimental Cell Research, vol. 317, no. 6, pp. 745–756, 2011.
[39]
A. W. James, P. Leucht, B. Levi et al., “Sonic hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells,” Tissue Engineering A, vol. 16, no. 8, pp. 2605–2616, 2010.
[40]
C. Fontaine, W. Cousin, M. Plaisant, C. Dani, and P. Peraldi, “Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells,” Stem Cells, vol. 26, no. 4, pp. 1037–1046, 2008.
[41]
A. W. James, A. Pan, M. Chiang et al., “A new function of Nell-1 protein in repressing adipogenic differentiation,” Biochemical and Biophysical Research Communications, vol. 411, no. 1, pp. 126–131, 2011.
[42]
A. W. James, S. Pang, A. Askarinam, et al., “Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells,” Stem Cells and Development, vol. 21, no. 12, pp. 2170–2178, 2012.
[43]
R. E. Jung, S. I. Windisch, A. M. Eggenschwiler, D. S. Thoma, F. E. Weber, and C. H. F. H？mmerle, “A randomized-controlled clinical trial evaluating clinical and radiological outcomes after 3 and 5 years of dental implants placed in bone regenerated by means of GBR techniques with or without the addition of BMP-2,” Clinical Oral Implants Research, vol. 20, no. 7, pp. 660–666, 2009.
[44]
P. C. Bessa, M. Casal, and R. L. Reis, “Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery),” Journal of Tissue Engineering and Regenerative Medicine, vol. 2, no. 2-3, pp. 81–96, 2008.
[45]
Q. Kang, W.-X. Song, Q. Luo et al., “A Comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells,” Stem Cells and Development, vol. 18, no. 4, pp. 545–558, 2009.
[46]
L. J. Dorman, M. Tucci, and H. Benghuzzi, “In vitro effects of bmp-2, bmp-, and bmp-13 on proliferation and differentation of mouse mesenchymal stem cells,” Biomedical Sciences Instrumentation, vol. 48, pp. 81–87, 2012.
[47]
D. Chen, X. Ji, M. A. Harris et al., “Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages,” Journal of Cell Biology, vol. 142, no. 1, pp. 295–305, 1998.
[48]
E. A. Wang, D. I. Israel, S. Kelly, and D. P. Luxenberg, “Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells,” Growth Factors, vol. 9, no. 1, pp. 57–71, 1993.
[49]
M. T. Valenti, U. Garbin, A. Pasini et al., “Role of Ox-PAPCs in the differentiation of mesenchymal stem cells (MSCs) and Runx2 and PPARγ2 expression in MSCs-like of osteoporotic patients,” PLoS ONE, vol. 6, no. 6, Article ID e20363, 2011.
[50]
L. Zhang, P. Su, C. Xu et al., “Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARγ expression and enhancing Runx2 expression,” Journal of Pineal Research, vol. 49, no. 4, pp. 364–372, 2010.
[51]
X. Li, Q. Cui, C. Kao, G.-J. Wang, and G. Balian, “Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARγ2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures,” Bone, vol. 33, no. 4, pp. 652–659, 2003.
[52]
X. Zhang, M. Yang, L. Lin et al., “Runx2 overexpression enhances osteoblastic differentiation and mineralization in adipose—derived stem cells in vitro and in vivo,” Calcified Tissue International, vol. 79, no. 3, pp. 169–178, 2006.
[53]
X. Zhou, Z. Zhang, J. Q. Feng et al., “Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 29, pp. 12919–12924, 2010.
[54]
G. J. Darlington, S. E. Ross, and O. A. MacDougald, “The role of C/EBP genes in adipocyte differentiation,” The Journal of Biological Chemistry, vol. 273, no. 46, pp. 30057–30060, 1998.
[55]
S. Wang, Q. Wang, B. E. Crute, I. N. Melnikova, S. R. Keller, and N. A. Speck, “Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor,” Molecular and Cellular Biology, vol. 13, no. 6, pp. 3324–3339, 1993.
[56]
S.-C. Bae, “Regulation mechanisms for the heterodimeric transcription factor, PEBP2/CBF,” Histology and Histopathology, vol. 14, no. 4, pp. 1213–1221, 1999.
[57]
E. Ogawa, M. Inuzuka, M. Maruyama et al., “Molecular cloning and characterization of PEBP2β, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2α,” Virology, vol. 194, no. 1, pp. 314–331, 1993.
[58]
T. E. North, T. Stacy, C. J. Matheny, N. A. Speck, and M. F. T. R. de Bruijn, “Runx1 Is expressed in adult mouse hematopoietic stem cells and differentiating myeloid and lymphoid cells, but not in maturing erythroid cells,” Stem Cells, vol. 22, no. 2, pp. 158–168, 2004.
[59]
C. A. Yoshida, H. Yamamoto, T. Fujita et al., “Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog,” Genes and Development, vol. 18, no. 8, pp. 952–963, 2004.
[60]
D. Levanon, D. Bettoun, C. Harris-Cerruti et al., “The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons,” EMBO Journal, vol. 21, no. 13, pp. 3454–3463, 2002.
[61]
O. Brenner, D. Levanon, V. Negreanu et al., “Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 45, pp. 16016–16021, 2004.
[62]
Y. Ito, “RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes,” Advances in Cancer Research, vol. 99, pp. 33–76, 2008.
[63]
K. Blyth, E. R. Cameron, and J. C. Neil, “The RUNX genes: gain or loss of function in cancer,” Nature Reviews Cancer, vol. 5, no. 5, pp. 376–387, 2005.
[64]
M. Stewart, A. Terry, M. Hu et al., “Proviral insertions induce the expression of bone-specific isoforms of PEBP2αA (CBFA1): evidence for a new myc collaborating oncogene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 16, pp. 8646–8651, 1997.
[65]
A. Goel, C. N. Arnold, P. Tassone et al., “Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers,” International Journal of Cancer, vol. 112, no. 5, pp. 754–759, 2004.
[66]
Q.-L. Li, H.-R. Kim, W.-J. Kim et al., “Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer,” Biochemical and Biophysical Research Communications, vol. 314, no. 1, pp. 223–228, 2004.
[67]
T. Y. Kim, H. J. Lee, K. S. Hwang et al., “Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma,” Laboratory Investigation, vol. 84, no. 4, pp. 479–484, 2004.
[68]
W.-H. Guo, L.-Q. Weng, K. Ito et al., “Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor,” Oncogene, vol. 21, no. 54, pp. 8351–8355, 2002.
[69]
K.-S. Lee, H.-J. Kim, Q.-L. Li et al., “Runx2 is a common target of transforming growth factor β1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12,” Molecular and Cellular Biology, vol. 20, no. 23, pp. 8783–8792, 2000.
[70]
T. Komori, “Regulation of osteoblast differentiation by runx2,” Advances in Experimental Medicine and Biology, vol. 658, pp. 43–49, 2010.
[71]
J. Pratap, J. J. Wixted, T. Gaur et al., “Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells,” Cancer Research, vol. 68, no. 19, pp. 7795–7802, 2008.
[72]
F. Otto, A. P. Thornell, T. Crompton et al., “Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development,” Cell, vol. 89, no. 5, pp. 765–771, 1997.
[73]
E. Hesse, H. Saito, R. Kiviranta et al., “Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity,” Journal of Cell Biology, vol. 191, no. 7, pp. 1271–1283, 2010.
[74]
X. Zhang, K. Ting, C. M. Bessette et al., “Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in Runx2+/- mice,” Journal of Bone and Mineral Research, vol. 26, no. 4, pp. 777–791, 2011.
[75]
P. Tontonoz and B. M. Spiegelman, “Fat and beyond: the diverse biology of PPARγ,” Annual Review of Biochemistry, vol. 77, pp. 289–312, 2008.
[76]
I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990.
[77]
M. Gottlicher, E. Widmark, Q. Li, and J.-A. Gustafsson, “Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 10, pp. 4653–4657, 1992.
[78]
C. K. Glass, D. W. Rose, and M. G. Rosenfeld, “Nuclear receptor coactivators,” Current Opinion in Cell Biology, vol. 9, no. 2, pp. 222–232, 1997.
[79]
A. Chawla and M. A. Lazar, “Peroxisome proliferator and retinoid signaling pathways co-regulate preadipocyte phenotype and survival,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 5, pp. 1786–1790, 1994.
[80]
M. Adams, C. T. Montague, J. B. Prins et al., “Activators of peroxisome proliferator-activated receptor γ have depot- specific effects on human preadipocyte differentiation,” Journal of Clinical Investigation, vol. 100, no. 12, pp. 3149–3153, 1997.
[81]
P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B. M. Spiegelman, “mPPARγ2: tissue-specific regulator of an adipocyte enhancer,” Genes and Development, vol. 8, no. 10, pp. 1224–1234, 1994.
[82]
P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994.
[83]
Y. Zhu, C. Qi, J. R. Korenberg, et al., “Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 17, pp. 7921–7925, 1995.
[84]
I. Tzameli, H. Fang, M. Ollero et al., “Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes,” The Journal of Biological Chemistry, vol. 279, no. 34, pp. 36093–36102, 2004.
[85]
F. J. Schopfer, Y. Lin, P. R. S. Baker et al., “Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor γ ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2340–2345, 2005.
[86]
J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” The Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
[87]
C. J. Walkey and B. M. Spiegelman, “A functional peroxisome proliferator-activated receptor-γ ligand-binding domain is not required for adipogenesis,” The Journal of Biological Chemistry, vol. 283, no. 36, pp. 24290–24294, 2008.
[88]
B. Lecka-Czernik, E. J. Moerman, D. F. Grant, J. M. Lehmann, S. C. Manolagas, and R. L. Jilka, “Divergent effects of selective peroxisome proliferator-activated receptor-γ2 ligands on adipocyte versus osteoblast differentiation,” Endocrinology, vol. 143, no. 6, pp. 2376–2384, 2002.
[89]
O. P. Lazarenko, S. O. Rzonca, L. J. Suva, and B. Lecka-Czernik, “Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat,” Bone, vol. 38, no. 1, pp. 74–84, 2006.
[90]
A. A. Ali, R. S. Weinstein, S. A. Stewart, A. M. Parfitt, S. C. Manolagas, and R. L. Jilka, “Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation,” Endocrinology, vol. 146, no. 3, pp. 1226–1235, 2005.
[91]
S. O. Rzonca, L. J. Suva, D. Gaddy, D. C. Montague, and B. Lecka-Czernik, “Bone is a target for the antidiabetic compound rosiglitazone,” Endocrinology, vol. 145, no. 1, pp. 401–406, 2004.
[92]
W. Kim, M. Kim, and E. H. Jho, “Wnt/beta-catenin signalling: from plasma membrane to nucleus,” Biochemical Journal, vol. 450, no. 1, pp. 9–21, 2013.
[93]
C. Niehrs, “The complex world of WNT receptor signalling,” Nature Reviews Molecular Cell Biology, vol. 13, no. 12, pp. 767–779.
[94]
D. C. Berwick and K. Harvey, “The importance of Wnt signalling for neurodegeneration in Parkinson's disease,” Biochemical Society Transactions, vol. 40, no. 5, pp. 1123–1128.
[95]
B. D. White, A. J. Chien, and D. W. Dawson, “Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers,” Gastroenterology, vol. 142, no. 2, pp. 219–232, 2012.
[96]
C. P. Xavier, M. Melikova, Y. Chuman, et al., “Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/beta-catenin signaling,” Cell Signal, vol. 26, no. 1, pp. 94–101, 2013.
[97]
P. Pandur, D. Maurus, and M. Kühl, “Increasingly complex: new players enter the Wnt signaling network,” BioEssays, vol. 24, no. 10, pp. 881–884, 2002.
[98]
S. L. Etheridge, G. J. Spencer, D. J. Heath, and P. G. Genever, “Expression profiling and functional analysis of Wnt signaling mechanisms in mesenchymal stem cells,” Stem Cells, vol. 22, no. 5, pp. 849–860, 2004.
[99]
H.-Y. Wang and C. C. Malbon, “Wnt-frizzled signaling to G-protein-coupled effectors,” Cellular and Molecular Life Sciences, vol. 61, no. 1, pp. 69–75, 2004.
[100]
F. Li, Z. Z. Chong, and K. Maiese, “Winding through the WNT pathway during cellular development and demise,” Histology and Histopathology, vol. 21, no. 1–3, pp. 103–124, 2006.
[101]
L. A. Davis and N. I. Zur Nieden, “Mesodermal fate decisions of a stem cell: the Wnt switch,” Cellular and Molecular Life Sciences, vol. 65, no. 17, pp. 2658–2674, 2008.
[102]
R. van Amerongen, “Alternative Wnt pathways and receptors,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 10, 2012.
[103]
N. Case and J. Rubin, “β-catenin—a supporting role in the skeleton,” Journal of Cellular Biochemistry, vol. 110, no. 3, pp. 545–553, 2010.
[104]
R. D. Little, J. P. Carulli, R. G. Del Mastro et al., “A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait,” American Journal of Human Genetics, vol. 70, no. 1, pp. 11–19, 2002.
[105]
Y. Gong, B. Roger, B. Slee, et al., “LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development,” Cell, vol. 107, no. 4, pp. 513–523, 2001.
[106]
L. M. Boyden, J. Mao, J. Belsky et al., “High bone density due to a mutation in LDL-receptor-related protein 5,” The New England Journal of Medicine, vol. 346, no. 20, pp. 1513–1521, 2002.
[107]
J. Chen and F. Long, “beta-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice,” Journal of Bone and Mineral Research, vol. 28, no. 5, pp. 1160–1169, 2013.
[108]
H. Hu, M. J. Hilton, X. Tu, K. Yu, D. M. Ornitz, and F. Long, “Sequential roles of Hedgehog and Wnt signaling in osteoblast development,” Development, vol. 132, no. 1, pp. 49–60, 2005.
[109]
T. F. Day, X. Guo, L. Garrett-Beal, and Y. Yang, “Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis,” Developmental Cell, vol. 8, no. 5, pp. 739–750, 2005.
[110]
T. P. Hill, D. Sp？ter, M. M. Taketo, W. Birchmeier, and C. Hartmann, “Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes,” Developmental Cell, vol. 8, no. 5, pp. 727–738, 2005.
[111]
S. L. Holmen, C. R. Zylstra, A. Mukherjee et al., “Essential role of β-catenin in postnatal bone acquisition,” The Journal of Biological Chemistry, vol. 280, no. 22, pp. 21162–21168, 2005.
[112]
D. A. Glass II, P. Bialek, J. D. Ahn et al., “Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation,” Developmental Cell, vol. 8, no. 5, pp. 751–764, 2005.
[113]
N. Takahashi, K. Maeda, A. Ishihara, S. Uehara, and Y. Kobayashi, “Regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals,” Frontiers in Bioscience, vol. 16, no. 1, pp. 21–30, 2011.
[114]
B. Nie, S. Zhou, X. Fang, et al., “Implication of receptor activator of NF-kappaB ligand in Wnt/beta-catenin pathway promoting osteoblast-like cell differentiation,” Journal of Huazhong University of Science and Technology, vol. 32, no. 6, pp. 818–822, 2012.
[115]
D. Gatti, O. Viapiana, E. Fracassi, et al., “Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab,” Journal of Bone and Mineral Research, vol. 27, no. 11, pp. 2259–2263, 2012.
[116]
V. Lim and B. L. Clarke, “New therapeutic targets for osteoporosis: beyond denosumab,” Maturitas, vol. 73, no. 3, pp. 269–272, 2012.
[117]
D. Padhi, G. Jang, B. Stouch, L. Fang, and E. Posvar, “Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody,” Journal of Bone and Mineral Research, vol. 26, no. 1, pp. 19–26, 2011.
[118]
S. E. Papapoulos, “Targeting sclerostin as potential treatment of osteoporosis,” Annals of the Rheumatic Diseases, vol. 70, no. 1, pp. i119–i122, 2011.
[119]
M. Laudes, “Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes,” Journal of Molecular Endocrinology, vol. 46, no. 2, pp. 65–72, 2011.
[120]
S. E. Ross, N. Hemati, K. A. Longo et al., “Inhibition of adipogenesis by Wnt signaling,” Science, vol. 289, no. 5481, pp. 950–953, 2000.
[121]
J. Liu and S. R. Farmer, “Regulating the balance between peroxisome proliferator-activated receptor γ and β-catenin signaling during adipogenesis: a glycogen synthase kinase 3β phosphorylation-defective mutant of β-catenin inhibits expression of a subset of adipogenic genes,” The Journal of Biological Chemistry, vol. 279, no. 43, pp. 45020–45027, 2004.
[122]
M. Laudes, “Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes,” Journal of Molecular Endocrinology, vol. 46, no. 2, pp. 65–72, 2011.
[123]
M. Moldes, Y. Zuo, R. F. Morrison et al., “Peroxisome-proliferator-activated receptor γ suppresses Wnt/β-catenin signalling during adipogenesis,” Biochemical Journal, vol. 376, no. 3, pp. 607–613, 2003.
[124]
C. N. Bennett, S. E. Ross, K. A. Longo et al., “Regulation of Wnt signaling during adipogenesis,” The Journal of Biological Chemistry, vol. 277, no. 34, pp. 30998–31004, 2002.
[125]
M. Kawai, S. Mushiakea, K. Bessho, et al., “Wnt/Lrp/beta-catenin signaling suppresses adipogenesis by inhibiting mutual activation of PPARgamma and C/EBPalpha,” Biochemical and Biophysical Research Communications, vol. 363, no. 2, pp. 276–282, 2007.
[126]
H.-X. Li, X. Luo, R.-X. Liu, Y.-J. Yang, and G.-S. Yang, “Roles of Wnt/β-catenin signaling in adipogenic differentiation potential of adipose-derived mesenchymal stem cells,” Molecular and Cellular Endocrinology, vol. 291, no. 1-2, pp. 116–124, 2008.
[127]
C. Galli, M. Piemontese, S. Lumetti, et al., “GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces,” Clinical Oral Implants Research, vol. 24, no. 8, pp. 921–927, 2013.
[128]
C. N. Bennett, H. Ouyang, Y. L. Ma et al., “Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation,” Journal of Bone and Mineral Research, vol. 22, no. 12, pp. 1924–1932, 2007.
[129]
W. P. Cawthorn, A. J. Bree, Y. Yao et al., “Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism,” Bone, vol. 50, no. 2, pp. 477–489, 2012.
[130]
C. H. M. Castro, C. S. Shin, J. P. Stains et al., “Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis,” Journal of Cell Science, vol. 117, no. 13, pp. 2853–2864, 2004.
[131]
B. Gustafson, B. Eliasson, and U. Smith, “Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis,” Diabetologia, vol. 53, no. 3, pp. 536–540, 2010.
[132]
I. Takada, M. Mihara, M. Suzawa et al., “A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation,” Nature Cell Biology, vol. 9, no. 11, pp. 1273–1285, 2007.
[133]
H. H.-C. Yao, W. Whoriskey, and B. Capel, “Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis,” Genes and Development, vol. 16, no. 11, pp. 1433–1440, 2002.
[134]
R. D. Riddle, R. L. Johnson, E. Laufer, and C. Tabin, “Sonic hedgehog mediates the polarizing activity of the ZPA,” Cell, vol. 75, no. 7, pp. 1401–1416, 1993.
[135]
M. Ruat, H. Roudaut, J. Ferent, and E. Traiffort, “Hedgehog trafficking, cilia and brain functions,” Differentiation, vol. 83, no. 2, pp. S97–S104, 2012.
[136]
M. J. Bitgood and A. P. McMahon, “Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo,” Developmental Biology, vol. 172, no. 1, pp. 126–138, 1995.
[137]
L. Nanni, J. E. Ming, M. Bocian et al., “The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly,” Human Molecular Genetics, vol. 8, no. 13, pp. 2479–2488, 1999.
[138]
F. Simpson, M. C. Kerr, and C. Wicking, “Trafficking, development and hedgehog,” Mechanisms of Development, vol. 126, no. 5-6, pp. 279–288, 2009.
[139]
S. Sinha and J. K. Chen, “Purmorphamine activates the Hedgehog pathway by targeting Smoothened,” Nature Chemical Biology, vol. 2, no. 1, pp. 29–30, 2006.
[140]
J. A. Pospisilik, D. Schramek, H. Schnidar et al., “Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate,” Cell, vol. 140, no. 1, pp. 148–160, 2010.
[141]
J. M. Suh, X. Gao, J. McKay, R. McKay, Z. Salo, and J. M. Graff, “Hedgehog signaling plays a conserved role in inhibiting fat formation,” Cell Metabolism, vol. 3, no. 1, pp. 25–34, 2006.
[142]
B. K. Zehentner, U. Leser, and H. Burtscher, “BMP-2 and sonic hedgehog have contrary effects on adipocyte-like differentiation of C3H10T1/2 cells,” DNA and Cell Biology, vol. 19, no. 5, pp. 275–281, 2000.
[143]
T. Yuasa, H. Kataoka, N. Kinto et al., “Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2,” Journal of Cellular Physiology, vol. 193, no. 2, pp. 225–232, 2002.
[144]
M. Zhao, M. Qiao, S. E. Harris, D. Chen, B. O. Oyajobi, and G. R. Mundy, “The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling,” Molecular and Cellular Biology, vol. 26, no. 16, pp. 6197–6208, 2006.
[145]
T. Nakamura, T. Aikawaa, M. Iwamoto-Enomoto, et al., “Induction of osteogenic differentiation by hedgehog proteins,” Biochemical and Biophysical Research Communications, vol. 237, no. 2, pp. 465–469, 1997.
[146]
N. Kinto, M. Iwamoto, M. Enomoto-Iwamoto et al., “Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation,” FEBS Letters, vol. 404, no. 2-3, pp. 319–323, 1997.
[147]
S. Spinella-Jaegle, G. Rawadi, S. Kawai et al., “Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation,” Journal of Cell Science, vol. 114, no. 11, pp. 2085–2094, 2001.
[148]
G. van der Horst, H. Farih-Sips, C. W. G. M. L？wik, and M. Karperien, “Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells,” Bone, vol. 33, no. 6, pp. 899–910, 2003.
[149]
T. Aghaloo, C. M. Cowan, Y.-F. Chou et al., “Nell-1-induced bone regeneration in calvarial defects,” American Journal of Pathology, vol. 169, no. 3, pp. 903–915, 2006.
[150]
K. Ting, H. Vastardis, J. B. Mulliken et al., “Human NELL-1 expressed in unilateral coronal synostosis,” Journal of Bone and Mineral Research, vol. 14, no. 1, pp. 80–89, 1999.
[151]
X. Zhang, J. Zara, R. K. Siu, K. Ting, and C. Soo, “The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration,” Journal of Dental Research, vol. 89, no. 9, pp. 865–878, 2010.
[152]
X. Zhang, S. Kuroda, D. Carpenter, et al., “Craniosynostosis in transgenic mice overexpressing Nell-1,” Journal of Clinical Investigation, vol. 110, no. 6, pp. 861–870, 2002.
[153]
X. Zhang, K. Ting, D. Pathmanathan et al., “Calvarial cleidocraniodysplasia-like defects with ENU-induced Nell-1 deficiency,” Journal of Craniofacial Surgery, vol. 23, no. 1, pp. 61–66, 2012.
[154]
S. S. Lu, X. Zhang, C. Soo et al., “The osteoinductive properties of Nell-1 in a rat spinal fusion model,” Spine Journal, vol. 7, no. 1, pp. 50–60, 2007.
[155]
R. K. Siu, S. S. Lu, W. Li et al., “Nell-1 protein promotes bone formation in a sheep spinal fusion model,” Tissue Engineering A, vol. 17, no. 7-8, pp. 1123–1135, 2011.
[156]
W. Li, J. N. Zara, R. K. Siu et al., “Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model,” Plastic and Reconstructive Surgery, vol. 127, no. 2, pp. 580–587, 2011.
[157]
M. Lee, W. Li, R. K. Siu et al., “Biomimetic apatite-coated alginate/chitosan microparticles as osteogenic protein carriers,” Biomaterials, vol. 30, no. 30, pp. 6094–6101, 2009.
[158]
W. Li, M. Lee, J. Whang et al., “Delivery of lyophilized nell-1 in a rat spinal fusion model,” Tissue Engineering A, vol. 16, no. 9, pp. 2861–2870, 2010.
[159]
J. Shen, W. Aaron, J. Chung, et al., “NELL-1 promotes cell adhesion and differentiation via Integrinbeta1,” Journal of Cellular Biochemistry, vol. 113, no. 12, pp. 3620–3628, 2012.
[160]
F. Chen, B. Walder, A. W. James, et al., “NELL-1-dependent mineralisation of Saos-2 human osteosarcoma cells is mediated via c-Jun N-terminal kinase pathway activation,” International Orthopaedics, vol. 36, no. 10, pp. 2181–2187, 2012.
[161]
A. W. James, et al., “A new mode of action of Nell-1 protein via potentiation of Canonical Wnt signaling,” Conferenece (Wnt '11), Los Angeles, Ca, USA, 2011.
[162]
C. M. Cowan, X. Zhangb, A. W. James, et al., “NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2,” Biochemical and Biophysical Research Communications, vol. 422, no. 3, pp. 351–357, 2012.
[163]
J. Kwak, J. N. Zara, M. Chiang, et al., “NELL-1 injection maintains long-bone quantity and quality in an ovariectomy-induced osteoporotic senile rat model,” Tissue Engineering A, vol. 19, no. 3-4, pp. 426–436, 2013.
[164]
J. M. Wozney, V. Rosen, A. J. Celeste et al., “Novel regulators of bone formation: molecular clones and activities,” Science, vol. 242, no. 4885, pp. 1528–1534, 1988.
[165]
D. Chen, M. Zhao, and G. R. Mundy, “Bone morphogenetic proteins,” Growth Factors, vol. 22, no. 4, pp. 233–241, 2004.
[166]
B. Bragdon, O. Moseychuk, S. Saldanha, D. King, J. Julian, and A. Nohe, “Bone morphogenetic proteins: a critical review,” Cellular Signalling, vol. 23, no. 4, pp. 609–620, 2011.
[167]
M. O. Freire, H.-K. You, J.-K. Kook, J.-H. Choi, and H. H. Zadeh, “Antibody-mediated osseous regeneration: a novel strategy for bioengineering bone by immobilized anti-bone morphogenetic protein-2 antibodies,” Tissue Engineering A, vol. 17, no. 23-24, pp. 2911–2918, 2011.
[168]
G. E. Friedlaender, C. R. Perry, J. D. Cole et al., “Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions,” The Journal of Bone and Joint Surgery, vol. 83, no. 2, pp. S151–158, 2001.
[169]
K. Miyazono, S. Maeda, and T. Imamura, “BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk,” Cytokine and Growth Factor Reviews, vol. 16, no. 3, pp. 251–263, 2005.
[170]
A. Nohe, E. Keating, P. Knaus, and N. O. Petersen, “Signal transduction of bone morphogenetic protein receptors,” Cellular Signalling, vol. 16, no. 3, pp. 291–299, 2004.
[171]
R. Nishimura, K. Hata, T. Matsubara, M. Wakabayashi, and T. Yoneda, “Regulation of bone and cartilage development by network between BMP signalling and transcription factors,” Journal of Biochemistry, vol. 151, no. 3, pp. 247–254, 2012.
[172]
X. Li and X. Cao, “BMP signaling and skeletogenesis,” Annals of the New York Academy of Sciences, vol. 1068, no. 1, pp. 26–40, 2006.
[173]
K. Hata, R. Nishimura, F. Ikeda et al., “Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor γ during bone morphogenetic protein 2-induced adipogenesis,” Molecular Biology of the Cell, vol. 14, no. 2, pp. 545–555, 2003.
[174]
W. Jin, T. Takagi, S.-N. Kanesashi et al., “Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins,” Developmental Cell, vol. 10, no. 4, pp. 461–471, 2006.
[175]
R. R. Bowers and M. D. Lane, “A role for bone morphogenetic protein-4 in adipocyte development,” Cell Cycle, vol. 6, no. 4, pp. 385–389, 2007.
[176]
R. R. Bowers, J. W. Kim, T. C. Otto, and M. D. Lane, “Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 35, pp. 13022–13027, 2006.
[177]
S. Herzig and C. Wolfrum, “Brown and white fat: from signaling to disease,” Biochim Biophys Acta, vol. 1831, no. 5, p. 895, 2013.
[178]
R. Hao, L. Yuan, N. Zhang, et al., “Brown adipose tissue: distribution and influencing factors on FDG PET/CT scan,” Journal of Pediatric Endocrinology and Metabolism, vol. 25, no. 3-4, pp. 233–237, 2012.
[179]
S. W. Qian, Y. Tang, X. Li, et al., “BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 9, pp. E798–E807, 2013.
[180]
M. Ahrens, T. Ankenbauer, D. Schroder, A. Hollnagel, H. Mayer, and G. Gross, “Expression of human bone morphogenetic proteins-2 or -4 in murine mesenchymal progenitor C3H10T 1/2 cells induces differentiation into distinct mesenchymal cell lineages,” DNA and Cell Biology, vol. 12, no. 10, pp. 871–880, 1993.
[181]
Y. Mishina, M. W. Starbuck, M. A. Gentile et al., “Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling,” The Journal of Biological Chemistry, vol. 279, no. 26, pp. 27560–27566, 2004.
[182]
M. Okamoto, J. Murai, H. Yoshikawa, and N. Tsumaki, “Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development,” Journal of Bone and Mineral Research, vol. 21, no. 7, pp. 1022–1033, 2006.
[183]
E. Gazzerro, A. Smerdel-Ramoya, S. Zanotti et al., “Conditional deletion of gremlin causes a transient increase in bone formation and bone mass,” The Journal of Biological Chemistry, vol. 282, no. 43, pp. 31549–31557, 2007.
[184]
E. Gazzerro, R. C. Pereira, V. Jorgetti, S. Olson, A. N. Economides, and E. Canalis, “Skeletal overexpression of gremlin impairs bone formation and causes osteopenia,” Endocrinology, vol. 146, no. 2, pp. 655–665, 2005.
[185]
S. W. Davis and S. A. Camper, “Noggin regulates Bmp4 activity during pituitary induction,” Developmental Biology, vol. 305, no. 1, pp. 145–160, 2007.
[186]
W. Zhu, J. Kim, C. Cheng et al., “Noggin regulation of bone morphogenetic protein (BMP) 2/7 heterodimer activity in vitro,” Bone, vol. 39, no. 1, pp. 61–71, 2006.
[187]
C. Cheng, “Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs),” Journal of Bone and Joint Surgery A, vol. 85, no. 8, pp. 1544–1552, 2004.
[188]
M. Suzawa, Y. Takeuchi, S. Fukumoto et al., “Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro,” Endocrinology, vol. 140, no. 5, pp. 2125–2133, 1999.
[189]
P. Ducy and G. Karsenty, “The family of bone morphogenetic proteins,” Kidney International, vol. 57, no. 6, pp. 2207–2214, 2000.
[190]
J. Reid, H. M. Gilmour, and S. Holt, “Primary non-specific ulcer of the small intestine,” Journal of the Royal College of Surgeons of Edinburgh, vol. 27, no. 4, pp. 228–232, 1982.
[191]
M. Varkey, C. Kucharski, T. Haque, W. Sebald, and H. Uluda？, “In vitro osteogenic response of rat bone marrow cells to bFGF and BMP-2 treatments,” Clinical Orthopaedics and Related Research, no. 443, pp. 113–123, 2006.
[192]
K. Partridge, X. Yang, N. M. P. Clarke et al., “Adenoviral BMP-2 gene transfer in mesenchymal stem cells: In vitro and in vivo bone formation on biodegradable polymer scaffolds,” Biochemical and Biophysical Research Communications, vol. 292, no. 1, pp. 144–152, 2002.
[193]
F. Wegman, A. Bijenhof, L. Schuijff, F. C. Oner, W. J. Dhert, and J. Alblas, “Osteogenic differentiation as a result of BMP-2 plasmid DNA based gene therapy in vitro and in vivo,” European Cells & Materials, vol. 21, pp. 230–242, 2011.
[194]
K.-H. Park, H. Kim, S. Moon, and K. Na, “Bone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering,” Journal of Bioscience and Bioengineering, vol. 108, no. 6, pp. 530–537, 2009.
[195]
Y. Tang, W. Tang, Y. Lin et al., “Combination of bone tissue engineering and BMP-2 gene transfection promotes bone healing in osteoporotic rats,” Cell Biology International, vol. 32, no. 9, pp. 1150–1157, 2008.
[196]
D. H. R. Kempen, L. Lu, T. E. Hefferan et al., “Retention of in vitro and in vivo BMP-2 bioactivities in sustained delivery vehicles for bone tissue engineering,” Biomaterials, vol. 29, no. 22, pp. 3245–3252, 2008.
[197]
S.-L. Cheng, J. Lou, N. M. Wright, C.-F. Lai, L. V. Avioli, and K. D. Riew, “In vitro and in vivo induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene,” Calcified Tissue International, vol. 68, no. 2, pp. 87–94, 2001.
[198]
D. No？l, D. Gazit, C. Bouquet et al., “Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells,” Stem Cells, vol. 22, no. 1, pp. 74–85, 2004.
[199]
A. M. Osyczka, D. L. Diefenderfer, G. Bhargave, and P. S. Leboy, “Different effects of BMP-2 on marrow stromal cells from human and rat bone,” Cells Tissues Organs, vol. 176, no. 1–3, pp. 109–119, 2004.
[200]
D. L. Deifenderfer, A. M. Osyczka, G. C. Reilly, and P. S. Leboy, “BMP responsiveness in human mesenchymal stem cells,” Connective Tissue Research, vol. 44, no. 1, pp. 305–311, 2003.
[201]
C. Chen, H. Uluda？, Z. Wang, and H. Jiang, “Noggin suppression decreases BMP-2-induced osteogenesis of human bone marrow-derived mesenchymal stem cells in vitro,” Journal of Cellular Biochemistry, vol. 113, no. 12, pp. 3672–3680, 2012.
[202]
S. Rahman, P. J. Czernik, Y. Lu, and B. Lecka-Czernik, “β-catenin directly sequesters adipocytic and insulin sensitizing activities but not osteoblastic activity of PPARγ2 in marrow mesenchymal stem cells,” PLoS ONE, vol. 7, no. 12, Article ID e51746.
[203]
S. Yakar, H. Kim, H. Zhao et al., “The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting,” Pediatric Nephrology, vol. 20, no. 3, pp. 251–254, 2005.
[204]
A. Giustina, G. Mazziotti, and E. Canalis, “Growth hormone, insulin-like growth factors, and the skeleton,” Endocrine Reviews, vol. 29, no. 5, pp. 535–559, 2008.
[205]
C. Livingstone, “Insulin-like growth factor-I (IGF-I) and clinical nutrition,” Clinical Science, vol. 125, no. 6, pp. 265–280, 2013.
[206]
M. Kawai and C. J. Rosen, “Insulin-like growth factor-I and bone: lessons from mice and men,” Pediatric Nephrology, vol. 24, no. 7, pp. 1277–1285, 2009.
[207]
K. E. Govoni, “Insulin-like growth factor-I molecular pathways in osteoblasts: potential targets for pharmacological manipulation,” Current Molecular Pharmacology, vol. 5, no. 2, pp. 143–152, 2012.
[208]
X.-D. Peng, P.-Z. Xu, M.-L. Chen et al., “Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2,” Genes and Development, vol. 17, no. 11, pp. 1352–1365, 2003.
[209]
N. Ghosh-Choudhury, S. L. Abboud, R. Nishimura, A. Celeste, L. Mahimainathan, and G. G. Choudhury, “Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription,” The Journal of Biological Chemistry, vol. 277, no. 36, pp. 33361–33368, 2002.
[210]
L. Xian, X. Wu, L. Pang, et al., “Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells,” Nature Medicine, vol. 18, no. 7, pp. 1095–1101, 2012.
[211]
D. D. Bikle and Y. Wang, “Insulin like growth factor-I: a critical mediator of the skeletal response to parathyroid hormone,” Current Molecular Pharmacology, vol. 5, no. 2, pp. 135–142, 2012.
[212]
A. Mukherjee and P. Rotwein, “Insulin-like growth factor binding protein-5 in osteogenesis: facilitator or inhibitor?” Growth Hormone and IGF Research, vol. 17, no. 3, pp. 179–185, 2007.
[213]
R. C. Mccarty, S. Gronthos, A. C. Zannettino, B. K. Foster, and C. J. Xian, “Characterisation and developmental potential of ovine bone marrow derived mesenchymal stem cells,” Journal of Cellular Physiology, vol. 219, no. 2, pp. 324–333, 2009.
[214]
J. Chen, K. Yuan, X. Mao, et al., “Serum response factor regulates bone formation via IGF-1 and Runx2 signals,” Journal of Bone and Mineral Research, vol. 27, no. 8, pp. 1659–1668, 2012.
[215]
B. Levi, A. W. James, D. C. Wan, J. P. Glotzbach, G. W. Commons, and M. T. Longaker, “Regulation of human adipose-derived stromal cell osteogenic differentiation by insulin-like growth factor-1 and platelet-derived growth factor-α,” Plastic and Reconstructive Surgery, vol. 126, no. 1, pp. 41–52, 2010.
[216]
S. Kumar and S. Ponnazhagan, “Mobilization of bone marrow mesenchymal stem cells in vivo augments bone healing in a mouse model of segmental bone defect,” Bone, vol. 50, no. 4, pp. 1012–1018, 2012.
[217]
A. Bernstein, H. O. Mayr, and R. Hube, “Can bone healing in distraction osteogenesis be accelerated by local application of IGF-1 and TGF-β1?” Journal of Biomedical Materials Research B, vol. 92, no. 1, pp. 215–225, 2010.
[218]
H.-W. Courtland, H. Sun, M. Beth-On et al., “Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production,” Journal of Bone and Mineral Research, vol. 26, no. 4, pp. 761–768, 2011.
[219]
C. G. Tahimic, Y. Wang, and D. D. Bikle, “Anabolic effects of IGF-1 signaling on the skeleton,” Frontiers in Endocrinology, vol. 4, article 6, 2013.
[220]
M. Wabitsch, H. Hauner, E. Heinze, and W. M. Teller, “The role of growth hormone/insulin-like growth factors in adipocyte differentiation,” Metabolism, vol. 44, no. 10, pp. 45–49, 1995.
[221]
S. J. Yang, C. Y. Chen, G. D. Chang, et al., “Activation of Akt by advanced glycation end products (AGEs): involvement of IGF-1 receptor and caveolin-1,” PLoS ONE, vol. 8, no. 3, Article ID e58100, 2013.
[222]
A. W. James, A. Pan, M. Chiang et al., “A new function of Nell-1 protein in repressing adipogenic differentiation,” Biochemical and Biophysical Research Communications, vol. 411, no. 1, pp. 126–131, 2011.
[223]
L. Xiao, T. Sobue, A. Esliger et al., “Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells,” Bone, vol. 47, no. 2, pp. 360–370, 2010.
[224]
L. Choy, J. Skillington, and R. Derynck, “Roles of autocrine TGF-β receptor and Smad signaling in adipocyte differentiation,” Journal of Cell Biology, vol. 149, no. 3, pp. 667–681, 2000.
[225]
F. Ugarte, M. Ryser, S. Thieme et al., “Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells,” Experimental Hematology, vol. 37, no. 7, pp. 867.e1–875.e1, 2009.
[226]
M. R. Byun, H. Jeong, S. J. Bae, A. R. Kim, E. S. Hwang, and J.-H. Hong, “TAZ is required for the osteogenic and anti-adipogenic activities of kaempferol,” Bone, vol. 50, no. 1, pp. 364–372, 2012.
[227]
S. Wang, J. Mu, Z. Fan et al., “Insulin-like growth factor 1 can promote the osteogenic differentiation and osteogenesis of stem cells from apical papilla,” Stem Cell Research, vol. 8, no. 3, pp. 346–356, 2012.
[228]
T. Teruel, A. M. Valverde, M. Benito, and M. Lorenzo, “Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures,” Biochemical Journal, vol. 319, no. 2, pp. 627–632, 1996.
[229]
Y.-L. Huang, R.-F. Qiu, W.-Y. Mai et al., “Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro,” Journal of Zhejiang University B, vol. 13, no. 1, pp. 20–28, 2012.
