Mạng lưới tín hiệu điều chỉnh quá trình tạo xương trong tế bào gốc trung mô

Journal of Cell Communication and Signaling - Tập 16 - Trang 47-61 - 2021
Sachin Thomas1, Bithiah Grace Jaganathan1
1Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India

Tóm tắt

Quá trình tạo xương là một sự kiện phát triển quan trọng dẫn đến sự hình thành xương. Các tế bào tạo xương hay còn gọi là tế bào osteoblast phát triển từ các tế bào gốc trung mô (MSCs) thông qua một quá trình có kiểm soát chặt chẽ do nhiều đường dẫn tín hiệu điều chỉnh. Sự cam kết theo dòng tế bào osteogenic của MSCs được điều khiển bởi các tương tác giữa tế bào với tế bào, các yếu tố paracrine, tín hiệu cơ học, hormone và cytokine có trong môi trường của chúng, kích hoạt một loạt các phân tử tín hiệu thuộc về protein chuyển hóa xương, Wnt, Hedgehog và tín hiệu Notch. Những đường dẫn tín hiệu này, cả về mặt độc lập cũng như phối hợp với các phân tử tín hiệu khác, điều chỉnh sự cam kết theo dòng osteogenic của MSCs bằng cách kích hoạt một số yếu tố phiên mã đặc hiệu cho dòng osteo. Ở đây, chúng tôi thảo luận về các đường dẫn tín hiệu chính điều chỉnh sự chuyển hóa osteogenic của MSCs và sự tương tác qua lại giữa chúng trong quá trình chuyển hóa osteogenic. Chúng tôi cũng bàn về cách mà các đường dẫn tín hiệu này có thể được điều chỉnh để cải thiện liệu pháp sửa chữa và tái sinh xương.

Từ khóa

#tế bào gốc trung mô #tạo xương #tín hiệu sinh học #tín hiệu tế bào #yếu tố phiên mã

Tài liệu tham khảo

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 Alman BA (2015) The role of hedgehog signalling in skeletal health and disease. Nat Rev Rheumatol 11(9):552–560 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 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 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 Balani DH, Ono N, Kronenberg HM (2017) Parathyroid hormone regulates fates of murine osteoblast precursors in vivo. J Clin Investig 127(9):3333–3344 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Cai H, Zou J, Wang W, Yang A (2021) BMP2 induces hMSC osteogenesis and matrix remodeling. Mol Med Rep 23(2):1–12 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 Canalis E, Parker K, Feng JQ, Zanotti S (2013b) Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154(2):623–634 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 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 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 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 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 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 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 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 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 Day TF, Yang Y (2008) Wnt and hedgehog signaling pathways in bone development. The J Bone Joint Surg 90(Suppl 1):19–24 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 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 Ding M, Wang X (2017) Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity. Oncol Lett 14(6):6327–6333 Ducy P, Zhang R, Ridall AL (1997) Osf2 / Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Ji Y, Ke Y, Gao S (2017) Intermittent activation of notch signaling promotes bone formation. Am J Trans Res 9(6):2933–2944 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 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 Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116(13):2627–2634 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 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 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 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 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 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 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 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 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 Li Wang YM, Fei L (2015) Osterix-Cre transgene causes craniofacial bone development defect. Calcif Tissue Int 96(2):129–137 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Rosen V (2006) BMP and BMP inhibitors in bone. Ann N Y Acad Sci 1068(1):19–25 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 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 Sethi JK, Vidal-puig A (2015) Wnt signalling and the control of cellular metabolism. Biochem Biophys Res Commun 427(1):1–17 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 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 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 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 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 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 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 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 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 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 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 Silva BC, Bilezikian JP (2015) Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 22:41–50 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT (2003) The BMP antagonist noggin regulates cranial suture fusion. Nature 422(6932):625–629 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 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 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 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 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 Yang J, Andre P, Ye L, Yang YZ (2015) The Hedgehog signalling pathway in bone formation. Int J Oral Sci 7(2):73–79 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 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 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 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 Zanotti S, Canalis E (2010) Notch and the skeleton. Mol Cell Biol 30(4):886–896 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 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 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 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 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 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 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 Zieba JT, Chen YT, Lee BH, Bae Y (2020) Notch signaling in skeletal development, homeostasis and pathogenesis. Biomolecules 10(2):1–18 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