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Signaling network regulating osteogenesis in mesenchymal stem cells

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  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

Osteogenesis is an important developmental event that results in bone formation. Bone forming cells or osteoblasts develop from mesenchymal stem cells (MSCs) through a highly controlled process regulated by several signaling pathways. The osteogenic lineage commitment of MSCs is controlled by cell–cell interactions, paracrine factors, mechanical signals, hormones, and cytokines present in their niche, which activate a plethora of signaling molecules belonging to bone morphogenetic proteins, Wnt, Hedgehog, and Notch signaling. These signaling pathways individually as well as in coordination with other signaling molecules, regulate the osteogenic lineage commitment of MSCs by activating several osteo-lineage specific transcription factors. Here, we discuss the key signaling pathways that regulate osteogenic differentiation of MSCs and the cross-talk between them during osteogenic differentiation. We also discuss how these signaling pathways can be modified for therapy for bone repair and regeneration.

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Abbreviations

AD-MSCs:

Adipose tissue-derived mesenchymal stem cells

ALP:

Alkaline phosphatase

ATF4:

Activating transcription factor 4

BM-MSCs:

Bone marrow-derived MSCs

BMP:

Bone morphogenetic protein

BMPR:

BMP receptor

BSP:

Bone sialoprotein

Cbfa1:

Core binding factor 1

Cntnap4:

Contactin associated protein family member 4

Col1:

Collagen type 1

Dkk1:

Dickkopf 1

Dlk1:

Delta homolog-like 1

Dll1/2/3:

Delta-like 1/2/3

Dlk5:

Distal-less homeobox 5

DNER:

Delta/Notch-like EGF-related receptor

ERK1/2:

Extracellular-signal regulated kinase1/2

FAK:

Focal adhesion kinase

FGF:

Fibroblast growth factor

FOXO:

Forkhead box type O

Fzd:

Frizzled

GSK3β:

Glycogen synthase kinase-3 β

Hey:

HES-related with a YRPF motif

Ihh:

Indian hedgehog

Jag1:

Jagged 1

JNK:

Jun amino-terminal kinase

LRP:

Low-density lipoprotein receptor-related protein

MAPK:

Mitogen activated protein kinase

MSCs:

Mesenchymal stem cells

NELL-1:

Neural epidermal growth factor-like 1 protein

NICD:

Notch intracellular domain

Opn:

Osteopontin

Ocn:

Osteocalcin

Osx:

Osterix

PCP:

Planar cell polarity

PPARγ:

Peroxisome proliferator-activated receptor gamma

PTH:

Parathyroid hormone

PTHrP:

Parathyroid hormone-related protein

Rbpjκ:

Recombination signal binding protein for immunoglobulin kappa J region

rhBMP:

Recombinant human BMP

ROCK:

Rho associated protein kinase

Runx2:

Runt-related transcription factor 2

sFRP:

Secreted frizzled-related protein

Shh:

Sonic hedgehog

SMO:

Smoothened

SOST:

Sclerostin

Sox9:

SRY box transcription factor 9

TGFβ:

Transforming growth factor β

WIF1:

Wnt-inhibitory factor 1

YAP/TAZ:

Yes-associated protein/transcriptional coactivator with PDZ-biding motif

References

  • Aihara K, Kuroda SI, Kanayama N, Matsuyama S, Tanizawa K, Horie M (2003) A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases. Brain Res Mol Brain Res 116(1–2):86–93

    CAS  PubMed  Google Scholar 

  • Alman BA (2015) The role of hedgehog signalling in skeletal health and disease. Nat Rev Rheumatol 11(9):552–560

    CAS  PubMed  Google Scholar 

  • Ann EJ, Kim HY, Choi YH, Kim MY, Mo JS, Jung J, Yoon JH, Kim SM, Moon JS, Seo MS, Hong JA, Jang WG, Shore P, Komori T, Koh JT, Park HS (2011) Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation. J Bone Miner Res 26(2):317–330

    CAS  PubMed  Google Scholar 

  • Arnsdorf EJ, Tummala P, Kwon RY, Jacobs CR (2009) Mechanically induced osteogenic differentiation - the role of RhoA, ROCKII and cytoskeletal dynamics. J Cell Sci 122(4):546–553

    CAS  PubMed  PubMed Central  Google Scholar 

  • Askarinam A, James AW, Zara JN, Goyal R, Corselli M, Pan A, Liang P, Chang L, Rackohn T, Stoker D, Zhang X, Ting K, Péault B, Soo C (2013) Human perivascular stem cells show enhanced osteogenesis and vasculogenesis with nel-like molecule i protein. Tissue Eng Part A 19(11–12):1386–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  • Balani DH, Ono N, Kronenberg HM (2017) Parathyroid hormone regulates fates of murine osteoblast precursors in vivo. J Clin Investig 127(9):3333–3344

    Google Scholar 

  • Balemans W, Ebeling M, Patel N, Hul EV, Olson P, Dioszegi M, Lacza C, Wuyts W, Ende JVD, Willems P, Paes-alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Hul WV (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10(5):537–544

    CAS  PubMed  Google Scholar 

  • Barreto S, Gonzalez-Vazquez A, Cameron AR, Cavanagh B, Murray DJ, O’Brien FJ (2017) Identification of the mechanisms by which age alters the mechanosensitivity of mesenchymal stromal cells on substrates of differing stiffness: Implications for osteogenesis and angiogenesis. Acta Biomater 53:59–69

    PubMed  Google Scholar 

  • Batsali AK, Pontikoglou C, Koutroulakis D, Pavlaki KI, Damianaki A, Mavroudi I, Alpantaki K, Kouvidi E, Kontakis G, Papadaki HA (2017) Differential expression of cell cycle and WNT pathway-related genes accounts for differences in the growth and differentiation potential of Wharton’s jelly and bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 8(1):1–17

    Google Scholar 

  • Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM (2014) Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS ONE. https://doi.org/10.1371/journal.pone.0115963

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O’Brien CA, Manolagas SC, Jilka RL (2003) Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts - a putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem 278(50):50259–50272

    CAS  PubMed  Google Scholar 

  • Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146(11):4577–4583

    CAS  PubMed  Google Scholar 

  • Bennett CN, Ouyang H, Ma YL, Zeng Q, Gerin I, Sousa KM, Lane TF, Krishnan V, Hankenson KD, MacDougald OA (2007) Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22(12):1924–1932

    CAS  PubMed  Google Scholar 

  • Bessa PC, Cerqueira MT, Rada T, Gomes ME, Neves NM, Nobre A, Reis RL, Casal M (2009) Expression, purification and osteogenic bioactivity of recombinant human BMP-4, -9, -10, -11 and -14. Protein Expr Purif 63(2):89–94

    CAS  PubMed  Google Scholar 

  • Bilkovski R, Schulte DM, Oberhauser F, Gomolka M, Udelhoven M, Hettich MM, Roth B, Heidenreich A, Gutschow C, Krone W, Laudes M (2010) Role of Wnt-5a in the determination of human mesenchymal stem cells into preadipocytes. J Biol Chem 285(9):6170–6178

    CAS  PubMed  Google Scholar 

  • Bitgood MJ, McMahon AP (1995) Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol 172(1):126–138

    CAS  PubMed  Google Scholar 

  • Boyan BD, Olivares-Navarrete R, Berger MB, Hyzy SL, Schwartz Z (2018) Role of Wnt11 during osteogenic differentiation of human mesenchymal stem cells on microstructured titanium surfaces. Sci Rep 8(1):1–11

    CAS  Google Scholar 

  • 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(20):1513–1521

    CAS  PubMed  Google Scholar 

  • Byun MR, Kim AR, Hwang J-H, Kim KM, Hwang ES, Hong J-H (2014) FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone 58:72–80

    CAS  PubMed  Google Scholar 

  • Cai JQ, Huang YZ, Chen XH, Xie HL, Zhu HM, Tang L, Yang ZM, Huang YC, Deng L (2012) Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int 36(4):349–355

    CAS  PubMed  Google Scholar 

  • Cai SX, Liu AR, He HL, Chen QH, Yang Y, Guo FM, Huang YZ, Liu L, Qiu HB (2014) Stable genetic alterations of β-catenin and ROR2 regulate the wnt pathway, affect the fate of MSCs. J Cell Physiol 229(6):791–800

    CAS  PubMed  Google Scholar 

  • Cai H, Zou J, Wang W, Yang A (2021) BMP2 induces hMSC osteogenesis and matrix remodeling. Mol Med Rep 23(2):1–12

    Google Scholar 

  • Canalis E, Adams DJ, Boskey A, Parker K, Kranz L, Zanotti S (2013a) Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodeling. J Biol Chem 288(35):25614–25625

    CAS  PubMed  PubMed Central  Google Scholar 

  • Canalis E, Parker K, Feng JQ, Zanotti S (2013b) Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154(2):623–634

    CAS  PubMed  Google Scholar 

  • Cao J, Wei Y, Lian J, Yang L, Zhang X, Xie J, Liu Q, Luo J, He B, Tang M (2017) Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling. Int J Mol Med 40(2):378–388

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibañez G, MacDougald OA (2012) Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism. Bone 50(2):477–489

    CAS  PubMed  Google Scholar 

  • Chen F, Zhang X, Sun S, Zara JN, Zou X, Chiu R, Culiat CT, Ting K, Soo C (2011) Nell-1, an osteoinductive factor, is a direct transcriptional target of osterix. PLoS ONE 6(9):1–11

    Google Scholar 

  • Chen SX, Feng JQ, Zhang H, Jia M, Shen Y, Zong ZW (2014) Key role for the transcriptional factor, osterix, in spine development. Spine J 14(4):683–694

    PubMed  Google Scholar 

  • Chen X, Hu Y, Jiang T, Xia C, Wang Y, Gao Y (2020) Triiodothyronine potentiates BMP9-induced osteogenesis in mesenchymal stem cells through the activation of AMPK/p38 signaling. Front Cell Dev Biol 8(July):1–10

    PubMed  PubMed Central  Google Scholar 

  • Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, Luu HH, An N, Breyer B, Vanichakarn P, Szatkowski JP, Park JY, He TC (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Series A 85(8):1544–1552

    Google Scholar 

  • Cho SW, Yang JY, Sun HJ, Jung JY, Her SJ, Cho HY, Choi HJ, Kim SW, Kim SY, Shin CS (2009) Wnt inhibitory factor (WIF)-1 inhibits osteoblastic differentiation in mouse embryonic mesenchymal cells. Bone 44(6):1069–1077

    CAS  PubMed  Google Scholar 

  • Cowan CM, Jiang X, Hsu T, Soo C, Zhang B, Joyce Z, Kuroda S, Wu B, Zhang Z, Zhang X (2007) Synergistic effects of nell-1 and BMP-2 on the osteogenic differentiation. J Bone Miner Res 22(6):918–930

    CAS  PubMed  Google Scholar 

  • Cowan CM, Zhang X, James AW, Mari Kim T, Sun N, Wu B, Ting K, Soo C (2012) NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochem Biophys Res Commun 422(3):351–357

    CAS  PubMed  Google Scholar 

  • Day TF, Yang Y (2008) Wnt and hedgehog signaling pathways in bone development. The J Bone Joint Surg 90(Suppl 1):19–24

    PubMed  Google Scholar 

  • Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8(5):739–750

    CAS  PubMed  Google Scholar 

  • Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584

  • Desai J, Shannon ME, Johnson MD, Ruff DW, Hughes LA, Kerley MK, Carpenter DA, Johnson DK, Rinchik EM, Culiat CT (2006) Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Hum Mol Genet 15(8):1329–1341

    CAS  PubMed  Google Scholar 

  • Ding M, Wang X (2017) Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity. Oncol Lett 14(6):6327–6333

    PubMed  PubMed Central  Google Scholar 

  • Ducy P, Zhang R, Ridall AL (1997) Osf2 / Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    CAS  PubMed  Google Scholar 

  • Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–184

    CAS  PubMed  Google Scholar 

  • Edgar CM, Chakravarthy V, Barnes G, Kakar S, Gerstenfeld LC, Einhorn TA (2007) Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells. Bone 40(5):1389–1398

    CAS  PubMed  PubMed Central  Google Scholar 

  • Engin F, Yao Z, Yang T, Zhou G, Bertin T, Jiang MM, Chen Y, Wang L, Zheng H, Sutton RE, Boyce BF, Lee B (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14(3):299–305

    CAS  PubMed  PubMed Central  Google Scholar 

  • Etheridge SL, Spencer GJ, Heath DJ, Genever PG (2004) Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells 22(5):849–860

    CAS  PubMed  Google Scholar 

  • Fan Y, Hanai J, i., Le, P. T., Bi, R., Maridas, D., DeMambro, V., Figueroa, C. A., Kir, S., Zhou, X., Mannstadt, M., Baron, R., Bronson, R. T., Horowitz, M. C., Wu, J. Y., Bilezikian, J. P., Dempster, D. W., Rosen, C. J. & Lanske, B. (2017) Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab 25(3):661–672

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fernandes H, Dechering K, Van Someren E, Steeghs I, Apotheker M, Mentink A, Van Blitterswijk C, De Boer J (2010) Effect of chordin-like 1 on MC3T3-E1 and human mesenchymal stem cells. Cells Tissues Organs 191(6):443–452

    CAS  PubMed  Google Scholar 

  • Figeac F, Andersen DC, Nipper Nielsen CA, Ditzel N, Sheikh SP, Skjødt K, Kassem M, Jensen CH, Abdallah BM (2018) Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice. Bone 110:312–320

    CAS  PubMed  Google Scholar 

  • Gao Y, Huang E, Zhang H, Wang J, Wu N, Chen X, Wang N, Wen S, Nan G, Deng F, Liao Z, Wu D, Zhang B, Zhang J, Haydon RC, Luu HH, Shi LL, He TC (2013) Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells. PLoS ONE 8(12):1–13

    Google Scholar 

  • Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN, Komm BS, Javed A, Van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. https://doi.org/10.1074/jbc.M500608200

    Article  PubMed  Google Scholar 

  • Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S, Baban K, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S (2002) Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420(6916):636–642

    CAS  PubMed  Google Scholar 

  • He Y, Zou L (2019) Notch-1 inhibition reduces proliferation and promotes osteogenic differentiation of bone marrow mesenchymal stem cells. Exp Therap Med 1859228:1884–1890

    Google Scholar 

  • Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, Fussenegger M, Deng X (2020) Role of YAP/TAZ in cell lineage fate determination and related signaling pathways. Front Cell Dev Biol 8:1–23

    Google Scholar 

  • Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R, Long F (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14(3):306–314

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holmen SL, Giambernardi TA, Zylstra CR, Buckner-berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO (2004) Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J Bone Miner Res 19:2033–2040

    CAS  PubMed  Google Scholar 

  • Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J (1999) A new secreted protein that binds to Wnt proteins and inhibits their activites. Nature 398(6726):431–436

    CAS  PubMed  Google Scholar 

  • Hsu DR, A. N. E., Xiaorong Wang, P. M. E., Harland & Richard, M. (1998) Xenopus dorsalizing factor gremlin identifies a novel family of secreted factors antagonizing BMP activity. Mol Cell 1(5):673–683

    CAS  PubMed  Google Scholar 

  • Huang X, Cen X, Zhang B, Liao Y, Zhao Z, Zhu G, Zhao Z, Liu J (2019) The roles of circRFWD2 and circINO80 during NELL-1-induced osteogenesis. J Cell Mol Med 23(12):8432–8441

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hui C-C, Joyner AL (1993) A mouse model of Greig cephalo–polysyndactyly syndrome: the extra–toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet 3(3):241–246

    CAS  PubMed  Google Scholar 

  • James AW, Leucht P, Levi B, Carre AL, Xu Y, Helms JA, Longaker MT (2010) Sonic hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A 16(8):2605–2616

    CAS  PubMed  PubMed Central  Google Scholar 

  • James AW, Pan A, Chiang M, Zara JN, Zhang X, Ting K, Soo C (2011) A new function of Nell-1 protein in repressing adipogenic differentiation. Biochem Biophys Res Commun 411(1):126–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • James AW, Pang S, Askarinam A, Corselli M, Zara JN, Goyal R, Chang L, Pan A, Shen J, Yuan W, Stoker D, Zhang X, Adams JS, Ting K, Soo C (2012) Additive effects of sonic hedgehog and nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev 21(12):2170–2178

    CAS  PubMed  PubMed Central  Google Scholar 

  • James AW, Shen J, Zhang X, Asatrian G, Goyal R, Kwak JH, Jiang L, Bengs B, Culiat CT, Turner AS, Seim HB, Wu BM, Lyons K, Adams JS, Ting K, Soo C (2015) NELL-1 in the treatment of osteoporotic bone loss. Nat Commun 6:1–14

    Google Scholar 

  • James AW, Chiang M, Asatrian G, Shen J, Goyal R, Chung CG, Chang L, Shrestha S, Turner AS, Seim HB, Zhang X, Wu BM, Ting K, Soo C (2016) Vertebral implantation of NELL-1 enhances bone formation in an osteoporotic sheep model. Tissue Eng Part A 22(11–12):840–849

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jan De Boer HJW, Van Clemens B (2004) Effects of Wnt signalling on proliferation and differentiation of human mesenchymal stem Cells. Tissue Eng. https://doi.org/10.1089/107632704323061753

    Article  PubMed  Google Scholar 

  • Ji Y, Ke Y, Gao S (2017) Intermittent activation of notch signaling promotes bone formation. Am J Trans Res 9(6):2933–2944

    CAS  Google Scholar 

  • Jiang T, Xia C, Chen X, Hu Y, Wang Y, Wu J, Chen S, Gao Y (2019a) Melatonin promotes the BMP9-induced osteogenic differentiation of mesenchymal stem cells by activating the AMPK/β-catenin signalling pathway. Stem Cell Res Ther 10(1):1–13

    Google Scholar 

  • Jiang ZL, Jin H, Liu ZS, Liu MY, Cao XF, Jiang YY, Bai HD, Zhang B, Li Y (2019b) Lentiviral-mediated Shh reverses the adverse effects of high glucose on osteoblast function and promotes bone formation via Sonic hedgehog signaling. Mol Med Reports 20(4):3265–3275

  • Kang S, Graham JM Jr, Olney AH, Biesecker LG (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15(3):266–268

    CAS  PubMed  Google Scholar 

  • Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116(13):2627–2634

    CAS  PubMed  Google Scholar 

  • Kawashima N, Noda S, Yamamoto M, Okiji T (2017) Properties of dental pulp-derived mesenchymal stem cells and the effects of culture conditions. J Endod 43(9):S31–S34

    PubMed  Google Scholar 

  • Kim WK, Meliton V, Bourquard N, Hahn TJ, Parhami F (2010) Hedgehog signaling and osteogenic differentiation in multipotent bone marrow stromal cells are inhibited by oxidative stress. J Cell Biochem 111(5):1199–1209

    CAS  PubMed  Google Scholar 

  • Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764

    CAS  PubMed  Google Scholar 

  • Kuo SW, Rimando MG, Liu YS, Lee OK (2017) Intermittent administration of parathyroid hormone 1–34 enhances osteogenesis of human mesenchymal stem cells by regulating protein kinase Cδ. Int J Mol Sci. https://doi.org/10.3390/ijms18102221

    Article  PubMed  PubMed Central  Google Scholar 

  • Lawal RA, Zhou X, Batey K, Hoffman CM, Georger MA, Radtke F, Hilton MJ, Xing L, Frisch BJ, Calvi LM (2017) The notch ligand jagged1 regulates the osteoblastic lineage by maintaining the osteoprogenitor pool. J Bone Miner Res 32(6):1320–1331

    CAS  PubMed  Google Scholar 

  • Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, Di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova J-L, Munnich A, Cormier-Daire V (2011) Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet 44:85–88

    PubMed  Google Scholar 

  • Lehmann K, Seemann P, Stricker S, Sammar M, Meyer B, Suring K, Majewski F, Tinschert S, Grzeschik KH, Muller D, Knaus P, Nurnberg P, Mundlos S (2003) Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Nat Acad Sci U S A 100(21):12277–12282

  • Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu Ke H, Li X, Richards WG (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39(4):754–766

    CAS  PubMed  Google Scholar 

  • Li C, Zheng Z, Ha P, Chen X, Jiang W, Sun S, Chen F, Asatrian G, Berthiaume EA, Kim JK, Chen EC, Pang S, Zhang X, Ting K, Soo C (2018) Neurexin superfamily cell membrane receptor contactin-associated protein like-4 (Cntnap4) Is involved in neural EGFL-Like 1 (Nell-1)-responsive osteogenesis. J Bone Min Res off J Am Soc Bone Min Res 33(10):1813–1825

    CAS  Google Scholar 

  • Li C, Zhang X, Zheng Z, Nguyen A, Ting K, Soo C (2019) Nell-1 is a key functional modulator in osteochondrogenesis and beyond. J Dent Res 98(13):1458–1468

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Wang YM, Fei L (2015) Osterix-Cre transgene causes craniofacial bone development defect. Calcif Tissue Int 96(2):129–137

    PubMed  Google Scholar 

  • Liang ST, Chen JR, Tsai JJ, Lai YH, Hsiao CD (2019) Overexpression of notch signaling induces hyperosteogeny in zebrafish. Int J Mol Sci 20(15):1–20

    Google Scholar 

  • Liao YP, Du WM, Hu Y, Li FS, Ma Y, Wang H, Zhu JH, Zhou Y, Li Q, Su YX, He BC (2019) CREB/Wnt10b mediates the effect of COX-2 on promoting BMP9-induced osteogenic differentiation via reducing adipogenic differentiation in mesenchymal stem cells. J Cell Biochem 120(6):9572–9587

    CAS  PubMed  Google Scholar 

  • Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y, Himeno M, Narai S, Yamaguchi A, Komori T (2001) Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol 155(1):157–166

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu G, Vijayakumar S, Grumolato L, Arroyave R, Qiao H, Akiri G, Aaronson SA (2009) Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. J Cell Biol 185(1):67–75

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Gao L, Zhao A, Zhang R, Ji B, Wang L, Zheng Y, Zeng B, Valenzuela RK, He L, Ma J (2014) Identification of duplication downstream of BMP2 in a Chinese family with Brachydactyly type A2 (BDA2). PLoS ONE 9(4):e94201–e94201

    PubMed  PubMed Central  Google Scholar 

  • Liu P, Ping Y, Ma M, Zhang D, Liu C, Zaidi S, Gao S, Ji Y, Lou F, Yu F, Lu P, Stachnik A, Bai M, Wei C, Zhang L, Wang K, Chen R, New MI, Rowe DW, Yuen T, Sun L, Zaidi M (2016) Anabolic actions of notch on mature bone. Proc Natl Acad Sci 113(15):E2152–E2161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maes C, Kobayashi T, Selig MK, Torrekens S, Sanford I, Mackem S, Carmeliet G, Kronenberg HM (2010) Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell 19(2):329–344

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez LM, Labovsky V, Fernández-Vallone VB, Choi CH, Amorós MA, Phillips C, Chasseing NA (2016) Mesenchymal stem cells as regulators of the bone marrow and bone components. Elsevier, Amstersam

    Google Scholar 

  • Matsuhashi S, Noji S, Koyama E, Myokai F, Ohuchi H, Taniguchi S, Hori K (1995) New gene, nel, encoding a M(r) 93 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos. Dev Dyn off Publ Am Assoc Anat 203(2):212–222

    CAS  Google Scholar 

  • Mawrie D, Kumar A, Magdalene D, Bhattacharyya J, Jaganathan BG (2016) Mesenchymal stem cells from human extra ocular muscle harbor neuroectodermal differentiation potential. PLoS ONE 11(6):1–15

    Google Scholar 

  • Mawrie D, Bhattacharjee K, Sharma A, Sharma R, Bhattacharyya J, Bhattacharjee H, Deori N, Kumar A, Jaganathan BG (2019) Human orbital adipose tissue-derived mesenchymal stem cells possess neuroectodermal differentiation and repair ability. Cell Tissue Res 378(3):531–542

    CAS  PubMed  Google Scholar 

  • McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. https://doi.org/10.1016/S1534-5807(04)00075-9

    Article  PubMed  Google Scholar 

  • McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM, McMahon AP (1998) Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev 12(10):1438–1452

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meyers CA, Sun Z, Chang L, Ding C, Lu A, Ting K, Pang S, James AW (2019) Age dependent effects of NELL-1 isoforms on bone marrow stromal cells. J Orthop 16(2):175–178

    PubMed  PubMed Central  Google Scholar 

  • Mizrahi O, Sheyn D, Tawackoli W, Kallai I, Oh A, Su S, Da X, Zarrini P, Cook-Wiens G, Gazit D, Gazit Z (2013) BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. Gene Ther 20(4):370–377

    CAS  PubMed  Google Scholar 

  • Morvan F, Boulukos K, Clément-Lacroix P, Roman SR, Suc-Royer I, Vayssière B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21(6):934–945

    CAS  PubMed  Google Scholar 

  • Muguruma Y, Hozumi K, Warita H, Yahata T, Uno T, Ito M, Ando K (2017) Maintenance of bone homeostasis by DLL1-mediated notch signaling. J Cell Physiol 232(9):2569–2580

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, Crombrugghe BD (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    CAS  PubMed  Google Scholar 

  • Nickel J, Mueller TD (2019) Specification of BMP signaling. Cells 8(12):1579

  • Nifuji A, Noda M (1999) Coordinated expression of noggin and bone morphogenetic proteins (BMPs) during early skeletogenesis and induction of noggin expression by BMP-7. J Bone Miner Res 14(12):2057–2066

    CAS  PubMed  Google Scholar 

  • Ogura K, Iimura T, Makino Y, Sugie-Oya A, Takakura A, Takao-Kawabata R, Ishizuya T, Moriyama K, Yamaguchi A (2016) Short-term intermittent administration of parathyroid hormone facilitates osteogenesis by different mechanisms in cancellous and cortical bone. Bone Rep 5:7–14

    PubMed  PubMed Central  Google Scholar 

  • Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GWH, Beddington RSP, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89(5):765–771

    CAS  PubMed  Google Scholar 

  • Pakvasa M, Alverdy A, Mostafa S, Wang E, Fu L, Li A, Oliveira L, Athiviraham A, Lee MJ, Wolf JM, He T-C, Ameer GA, Reid RR (2017) Neural EGF-like protein 1 (NELL-1): signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine. Genes Dis 4(3):127–137

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pang S, Shen J, Liu Y, Chen F, Zheng Z, James AW, Hsu CY, Zhang H, Lee KS, Wang C, Li C, Chen X, Jia H, Zhang X, Soo C, Ting K (2015) Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1. Stem Cells 33(3):904–915

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pereira RC, Rydziel S, Canalis E (2000) Bone morphogenetic protein-4 regulates its own expression in cultured osteoblasts. J Cell Physiol 182(2):239–246

    CAS  PubMed  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(April):143–148

    CAS  PubMed  Google Scholar 

  • Qiang YW, Barlogie B, Rudikoff S, Shaughnessy JD (2008) Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. Bone 42(4):669–680

    CAS  PubMed  Google Scholar 

  • Qin X, Jiang Q, Miyazaki T, Komori T (2018) Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells. Hum Mol Genet 28(6):896–911

    Google Scholar 

  • Rebelatto CK, Aguiar AM, Moretão MP, Senegaglia AC, Hansen P, Barchiki F, Oliveira J, Martins J, Kuligovski C, Mansur F, Christofis A, Amaral VF, Brofman PS, Goldenberg S, Nakao LS, Correa A (2008) Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp Biol Med 233(7):901–913

    CAS  Google Scholar 

  • Riddle RC, Diegel CR, Leslie JM, Koevering KKV, Faugere M-C, Clemens TL, Williams BO (2013) Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. PLoS ONE. https://doi.org/10.1371/journal.pone.0063323

    Article  PubMed  PubMed Central  Google Scholar 

  • Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283(9):5866–5875

    CAS  PubMed  Google Scholar 

  • Rodríguez-Carballo E, Ulsamer A, Susperregui ARG, Manzanares-Céspedes C, Sánchez-García E, Bartrons R, Rosa JL, Ventura F (2011) Conserved regulatory motifs in osteogenic gene promoters integrate cooperative effects of canonical Wnt and BMP pathways. J Bone Miner Res 26(4):718–729

    PubMed  Google Scholar 

  • Rosen V (2006) BMP and BMP inhibitors in bone. Ann N Y Acad Sci 1068(1):19–25

    CAS  PubMed  Google Scholar 

  • Schneider H, Sedaghati B, Naumann A, Hacker MC, Schulz-Siegmund M (2014) Gene silencing of chordin improves BMP-2 effects on osteogenic differentiation of human adipose tissue-derived stromal cells. Tissue Eng Part A 20(1–2):335–345

    CAS  PubMed  Google Scholar 

  • Semenova D, Bogdanova M, Kostina A, Golovkin A, Kostareva A, Malashicheva A (2020) Dose-dependent mechanism of Notch action in promoting osteogenic differentiation of mesenchymal stem cells. Cell Tissue Res 379(1):169–179

    CAS  PubMed  Google Scholar 

  • Sethi JK, Vidal-puig A (2015) Wnt signalling and the control of cellular metabolism. Biochem Biophys Res Commun 427(1):1–17

    Google Scholar 

  • Shao J, Zhou Y, Lin J, Nguyen TD, Huang R, Gu Y, Friis T, Crawford R, Xiao Y (2018) Notch expressed by osteocytes plays a critical role in mineralisation. J Mol Med 96(3):333–347

    CAS  PubMed  Google Scholar 

  • Sharff KA, Song WX, Luo X, Tang N, Luo J, Chen J, Bi Y, He BC, Huang J, Li X, Jian W, Zhu GH, Su Y, He Y, Shen J, Wang Y, Chen L, Zuo GW, Liu B, Pan X, Reid RR, Luu HH, Haydon RC, He TC (2009) Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. J Biol Chem 284(1):649–659

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shea CM, Edgar CM, Einhorn TA, Gerstenfeld LC (2003) BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis. J Cell Biochem 90(6):1112–1127

    CAS  PubMed  Google Scholar 

  • Shen B, Bhargav D, Wei A, Williams LA, Tao H, Ma DDF, Ashish D (2009) BMP-13 emerges as a potential inhibitor of bone formation. Int J Biol Sci 5(2):192–200

    PubMed  PubMed Central  Google Scholar 

  • Shen J, James AW, Zhang X, Pang S, Zara JN, Asatrian G, Chiang M, Lee M, Khadarian K, Nguyen A, Lee KS, Siu RK, Tetradis S, Ting K, Soo C (2016) Novel wnt regulator NEL-like molecule-1 antagonizes adipogenesis and augments osteogenesis induced by bone morphogenetic protein 2. Am J Pathol 186(2):419–434

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen MJ, Wang GG, Wang YZ, Xie J, Ding X (2018) Nell-1 enhances osteogenic differentiation of pre-osteoblasts on titanium surfaces via the MAPK-ERK signaling pathway. Cell Physiol Biochem 50(4):1522–1534

    CAS  PubMed  Google Scholar 

  • Shi Y, Li H, Zhang X, Fu Y, Huang Y, Lui PPY, Tang T, Dai K (2011) Continuous cyclic mechanical tension inhibited Runx2 expression in mesenchymal stem cells through RhoA-ERK1/2 pathway. J Cell Physiol 226(8):2159–2169

    CAS  PubMed  Google Scholar 

  • Shih YRV, Tseng KF, Lai HY, Lin CH, Lee OK (2011) Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells. J Bone Min Res 26(4):730–738

  • Shima WN, Ali AM, Subramani T, Alitheen NBM, Hamid M, Samsudin AR, Yeap SK (2015) Rapid growth and osteogenic differentiation of mesenchymal stem cells isolated from human bone marrow. Exp Ther Med 9(6):2202–2206

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shimoyama A, Wada M, Ikeda F, Hata K, Matsubara T, Nifuji A, Noda M, Amano K, Yamaguchi A, Nishimura R, Yoneda T (2007) Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell 18:2411–2418

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527

    CAS  PubMed  Google Scholar 

  • Si ZZ, Wang X, Sun CH, Kang YC, Xu JK, Wang XD, Hui Y (2019) Adipose-derived stem cells: sources, potency, and implications for regenerative therapies. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2019.108765

    Article  PubMed  Google Scholar 

  • Silva BC, Bilezikian JP (2015) Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 22:41–50

    CAS  PubMed  PubMed Central  Google Scholar 

  • Simmons CA, Matlis S, Thornton AJ, Chen S, Wang CY, Mooney DJ (2003) Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. J Biomech 36(8):1087–1096

    PubMed  Google Scholar 

  • Somaiah C, Kumar A, Mawrie D, Sharma A, Patil SD, Bhattacharyya J, Swaminathan R, Jaganathan BG (2015) Collagen promotes higher adhesion, survival and proliferation of mesenchymal stem cells. PLoS ONE 10(12):1–15

    Google Scholar 

  • Song L, Liu M, Ono N, Bringhurst FR, Kronenberg HM, Guo J (2012) Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. J Bone Miner Res 27(11):2344–2358

    CAS  PubMed  Google Scholar 

  • Sonowal H, Kumar A, Bhattacharyya J, Gogoi PK, Jaganathan BG (2013) Inhibition of actin polymerization decreases osteogeneic differentiation of mesenchymal stem cells through p38 MAPK pathway. J Biomed Sci. https://doi.org/10.1186/1423-0127-20-71

    Article  PubMed  PubMed Central  Google Scholar 

  • St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13(16):2072–2086

    CAS  PubMed  PubMed Central  Google Scholar 

  • Su Z, He L, Shang H, Dai T, Xu F, Zhao J (2020) Overexpression of bone morphogenetic protein-1 promotes osteogenesis of bone marrow mesenchymal stem cells in vitro. Med Sci Monit 26:1–8

    Google Scholar 

  • Sugimoto A, Miyazaki A, Kawarabayashi K, Shono M, Akazawa Y, Hasegawa T, Ueda-Yamaguchi K, Kitamura T, Yoshizaki K, Fukumoto S, Iwamoto T (2017) Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells. Sci Rep 7(1):1–14

    Google Scholar 

  • Sukarawan W, Peetiakarawach K, Pavasant P, Osathanon T (2016) Effect of Jagged-1 and Dll-1 on osteogenic differentiation by stem cells from human exfoliated deciduous teeth. Arch Oral Biol 65:1–8

    CAS  PubMed  Google Scholar 

  • Tang N, Song WX, Luo J, Luo X, Chen J, Sharff KA, Bi Y, He BC, Huang JY, Zhu GH, Su YX, Jiang W, Tang M, He Y, Wang Y, Chen L, Zuo GW, Shen J, Pan X, Reid RR, Luu HH, Haydon RC, He TC (2009) BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/β-catenin signalling. J Cell Mol Med 13(8):2448–2464

    PubMed  Google Scholar 

  • Tang Z, Wei J, Yu Y, Zhang J, Liu L, Tang W, Long J, Zheng X, Jing W (2016) γ-Secretase inhibitor reverts the Notch signaling attenuation of osteogenic differentiation in aged bone marrow mesenchymal stem cells. Cell Biol Int 40(4):439–447

    CAS  PubMed  Google Scholar 

  • Tanjaya J, Lord EL, Wang C, Zhang Y, Kim JK, Nguyen A, Baik L, Pan HC, Chen E, Kwak JH, Zhang X, Wu B, Soo C, Ting K (2018) The effects of systemic therapy of PEGylated NEL-like protein 1 (NELL-1) on fracture healing in mice. Am J Pathol 188(3):715–727

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tao J, Chen S, Yang T, Dawson B, Munivez E, Bertin T, Lee B (2010) Osteosclerosis owing to notch gain of function is solely Rbpj-dependent. J Bone Miner Res 25(10):2175–2183

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tezuka KI, Yasuda M, Watanabe N, Morimura N, Kuroda K, Miyatani S, Hozumi N (2002) Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res 17(2):231–239

    CAS  PubMed  Google Scholar 

  • Tian Y, Xu Y, Fu Q, Dong Y (2012) Osterix is required for sonic hedgehog-induced osteoblastic MC3T3-E1 cell differentiation. Cell Biochem Biophys 64(3):169–176

    CAS  PubMed  Google Scholar 

  • Ting K, Vastardis H, Mulliken JB, Soo C, Tieu A, Do H, Kwong E, Bertolami CN, Kawamoto H, Kuroda S, i. & Longaker, M. T. (1999) Human NELL-1 expressed in unilateral coronal synostosis. J Bone Miner Res 14(1):80–89

    CAS  PubMed  Google Scholar 

  • Truong T, Zhang X, Pathmanathan D, Soo C, Ting K (2007) Craniosynostosis-associated gene Nell-1 is regulated by Runx2. J Bone Miner Res 22(1):7–18

    CAS  PubMed  Google Scholar 

  • Ulrich C, Abruzzese T, Maerz JK, Ruh M, Amend B, Benz K, Rolauffs B, Abele H, Hart ML, Aicher WK (2015) Human placenta-derived CD146-positive mesenchymal stromal cells display a distinct osteogenic differentiation potential. Stem Cells Dev 24(13):1558–1569

    CAS  PubMed  Google Scholar 

  • Vaes BLT, Dechering KJ, Someren EPV, Hendriks MA, Ven CJJMVD, Feijen A, Mummery CL, Reinders MJT, Olijve W, Zoelen EJJV, Steegenga WT (2005) Microarray analysis reveals expression regulation of Wnt antagonists in differentiating osteoblasts. Bone 36:803–811

    CAS  PubMed  Google Scholar 

  • Van Bezooijen RL, Roelen BAJ, Visser A, Van Der Wee-Pals L, De Wilt E, Karperien M, Hamersma H, Papapoulos SE, Ten Dijke P, Löwik CWGM (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199(6):805–814

    PubMed  PubMed Central  Google Scholar 

  • van der Horst G, van der Werf SM, Farih-Sips H, van Bezooijen RL, Löwik CW, Karperien M (2005) Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res 20(10):1867–1877

    PubMed  Google Scholar 

  • Wang Y, Hong SQ, Li M, Zhang JY, Bi Y, He Y, Liu X, Nan GX, Su YX, Zhu GH, Li RD, Zhang WW, Wang JH, Zhang HY, Kong YH, Shui W, Wu NN, He YF, Chen X, Luu HH, Haydon RC, Shi LL, He TC, Qin JQ (2013) Noggin resistance contributes to the potent osteogenic capability of BMP9 in mesenchymal stem cells. J Orthop Res 31(11):1796–1803

    PubMed  Google Scholar 

  • Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O, Li M, Shen C, Hu A, Haydon RC, Kang R, Mok J, Lee MJ, Luu HL, Shi LL (2014) Bone Morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 1(1):87–105

    PubMed  PubMed Central  Google Scholar 

  • Wang C, Inzana JA, Mirando AJ, Ren Y, Liu Z, Shen J, O’Keefe RJ, Awad HA, Hilton MJ, O’Keefe RJ, Awad HA, Hilton MJ (2016a) Notch signaling in skeletal progenitors is critical for fracture repair. J Clin Investig 126(4):1471–1481

    PubMed  PubMed Central  Google Scholar 

  • Wang Y, He T, Liu J, Liu H, Zhou L, Hao W, Sun Y, Wang X (2016b) Synergistic effects of overexpression of BMP-2 and TGF-β3 on osteogenic differentiation of bone marrow mesenchymal stem cells. Mol Med Rep 14(6):5514–5520

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang CL, Xiao F, Wang CD, Zhu JF, Shen C, Zuo B, Wang H, Li D, Wang XY, Feng WJ, Li ZK, Hu GL, Zhang X, Chen XD (2017) Gremlin2 suppression increases the BMP-2-induced osteogenesis of human bone marrow-derived mesenchymal stem cells via the BMP-2/Smad/Runx2 signaling pathway. J Cell Biochem 118(2):286–297

    CAS  PubMed  Google Scholar 

  • Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT (2003) The BMP antagonist noggin regulates cranial suture fusion. Nature 422(6932):625–629

    CAS  PubMed  Google Scholar 

  • Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22(23):6267–6276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xia K, Cen X, Yu L, Huang X, Sun W, Zhao Z, Liu J (2020) Long noncoding RNA expression profiles during the NEL-like 1 protein-induced osteogenic differentiation. J Cell Physiol 235(9):6010–6022

    CAS  PubMed  Google Scholar 

  • Xie Z, Wang P, Li Y, Deng W, Zhang X, Su H, Li D, Wu Y, Shen H (2016) Imbalance between bone morphogenetic protein 2 and noggin induces abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis. Arthr Rheumatol 68(2):430–440

    CAS  Google Scholar 

  • Xu N, Liu H, Qu F, Fan J, Mao K, Yin Y, Liu J, Geng Z, Wang Y (2013) Hypoxia inhibits the differentiation of mesenchymal stem cells into osteoblasts by activation of Notch signaling. Exp Mol Pathol 94(1):33–39

    CAS  PubMed  Google Scholar 

  • Xu L, Liu Y, Sun Y, Wang B, Xiong Y, Lin W, Wei Q, Wang H, He W, Wang B, Li G (2017) Tissue source determines the differentiation potentials of mesenchymal stem cells: A comparative study of human mesenchymal stem cells from bone marrow and adipose tissue. Stem Cell Res Ther 8(1):1–11

    Google Scholar 

  • Yang J, Andre P, Ye L, Yang YZ (2015) The Hedgehog signalling pathway in bone formation. Int J Oral Sci 7(2):73–79

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang MY, Arai A, Udagawa N, Zhao LJ, Nishida D, Murakami K, Hiraga T, Takao-Kawabata R, Matsuo K, Komori T, Kobayashi Y, Takahashi N, Isogai Y, Ishizuya T, Yamaguchi A, Mizoguchi T (2019) Parathyroid hormone shifts cell fate of a leptin receptor-marked stromal population from adipogenic to osteoblastic lineage. J Bone Miner Res 34(10):1952–1963

    CAS  PubMed  Google Scholar 

  • Youngstrom DW, Dishowitz MI, Bales CB, Carr E, Mutyaba PL, Kozloff KM, Shitaye H, Hankenson KD, Loomes KM (2016) Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone 91:64–74

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu B, Zhao X, Yang C, Crane J, Xian L, Lu W, Mei Wan A, Cao X (2012) PTH induces differentiation of mesenchymal stem cells by enhancing BMP signaling. J Bone Miner Res 27(9):2001–2014

    CAS  PubMed  Google Scholar 

  • Yuasa T, Kataoka H, Kinto N, Iwamoto M, Enomoto-Iwamoto M, Iemura S-I, Ueno N, Shibata Y, Kurosawa H, Yamaguchi A (2002) Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2. J Cell Physiol 193(2):225–232

    CAS  PubMed  Google Scholar 

  • Zanotti S, Canalis E (2010) Notch and the skeleton. Mol Cell Biol 30(4):886–896

    CAS  PubMed  Google Scholar 

  • Zanotti S, Smerdel-Ramoya A, Stadmeyer L, Durant D, Radtke F, Canalis E (2008) Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology 149(8):3890–3899

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Zara J, Siu RK, Ting K, Soo C (2010) The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration. J Dent Res 89(9):865–878

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Ting K, Bessette CM, Culiat CT, Sung SJ, Lee H, Chen F, Shen J, Wang JJ, Kuroda SI, Soo C (2011) Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in Runx2+/- mice. J Bone Miner Res 26(4):777–791

    CAS  PubMed  Google Scholar 

  • Zhao M, Qiao M, Harris SE, Chen D, Oyajobi BO, Mundy GR (2006) The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 Expression in osteoblasts in response to hedgehog signaling. Mol Cell Biol 26(16):6197–6208

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Yi FZ, Zhao YH, Chen YJ, Ma H, Zhang M (2016) The distinct effects of estrogen and hydrostatic pressure on mesenchymal stem cells differentiation: involvement of estrogen receptor signaling. Ann Biomed Eng 44(10):2971–2983

    PubMed  Google Scholar 

  • Zhong Z, Zylstra-diegel CR, Schumacher CA, Baker JJ, Carpenter AC (2012) Wntless functions in mature osteoblasts to regulate bone mass. PNAS 109(33):2197–2204

    Google Scholar 

  • Zhu Y, Wu Y, Cheng J, Wang Q, Li Z, Wang Y, Wang D, Wang H, Zhang W, Ye J, Jiang H, Wang L (2018) Pharmacological activation of TAZ enhances osteogenic differentiation and bone formation of adipose-derived stem cells. Stem Cell Res Ther 9(1):1–16

    Google Scholar 

  • Zieba JT, Chen YT, Lee BH, Bae Y (2020) Notch signaling in skeletal development, homeostasis and pathogenesis. Biomolecules 10(2):1–18

    Google Scholar 

  • Zou X, Shen J, Chen F, Ting K, Zheng Z, Pang S, Zara JN, Adams JS, Soo C, Zhang X (2011) NELL-1 binds to APR3 affecting human osteoblast proliferation and differentiation. FEBS Lett 585(15):2410–2418

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Amit Sharma for help with the figures. ST was supported by Ministry of Education (MoE), Govt. of India. This study was partially supported by Indian Institute of Technology Guwahati (IITG).

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  1. Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India

    Sachin Thomas & Bithiah Grace Jaganathan

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BGJ conceptualized the idea. ST and BGJ wrote the manuscript and approved the final version of the manuscript.

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Thomas, S., Jaganathan, B.G. Signaling network regulating osteogenesis in mesenchymal stem cells. J. Cell Commun. Signal. 16, 47–61 (2022). https://doi.org/10.1007/s12079-021-00635-1

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