{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:22:46Z","timestamp":1780935766594,"version":"3.54.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Growth factors such as transforming growth factor beta1 (TGF-<jats:italic>\u03b2<\/jats:italic>1), have critical roles in the regulation of the chondrogenic differentiation of mesenchymal stem cells (MSCs), which promote cartilage repair. However, the clinical applications of the traditional growth factors are limited by their high cost, functional heterogeneity and unpredictable effects, such as cyst formation. It may be advantageous for cartilage regeneration to identify a low-cost substitute with greater chondral specificity and easy accessibility. As a neuropeptide, nerve growth factor (NGF) was involved in cartilage metabolism and NGF is hypothesized to mediate the chondrogenic differentiation of MSCs. We isolated NGF from Chinese cobra venom using a three-step procedure that we had improved upon from previous studies, and investigated the chondrogenic potential of NGF on bone marrow MSCs (BMSCs) both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. The results showed that NGF greatly upregulated the expression of cartilage-specific markers. When applied to cartilage repair for 4, 8 and 12 weeks, NGF-treated BMSCs have greater therapeutic effect than untreated BMSCs. Although inferior to TGF-<jats:italic>\u03b2<\/jats:italic>1 regarding its chondrogenic potential, NGF showed considerably lower expression of collagen type I, which is a fibrocartilage marker, and<jats:italic>RUNX2<\/jats:italic>, which is critical for terminal chondrocyte differentiation than TGF-<jats:italic>\u03b2<\/jats:italic>1, indicating its chondral specificity. Interestingly, NGF rarely induced BMSCs to differentiate into a neuronal phenotype, which may be due to the presence of other chondrogenic supplements. Furthermore, the underlying mechanism revealed that NGF-mediated chondrogenesis may be associated with the activation of PI3K\/AKT and MAPK\/ERK signaling pathways via the specific receptor of NGF, TrkA. In addition, NGF is easily accessed because of the abundance and low price of cobra venom, as well as the simplified methods for separation and purification. This study was the first to demonstrate the chondrogenic potential of NGF, which may provide a reference for cartilage regeneration in the clinic.<\/jats:p>","DOI":"10.1038\/cddis.2017.208","type":"journal-article","created":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T12:43:35Z","timestamp":1495111415000},"page":"e2801-e2801","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Nerve growth factor from Chinese cobra venom stimulates chondrogenic differentiation of mesenchymal stem cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Zhenhui","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danqing","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongmeng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinmin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,18]]},"reference":[{"key":"BFcddis2017208_CR1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/jcp.21200","volume":"213","author":"AI Caplan","year":"2007","unstructured":"Caplan AI . Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 2007; 213: 341\u2013347.","journal-title":"J Cell Physiol"},{"key":"BFcddis2017208_CR2","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1016\/j.joca.2007.04.019","volume":"15","author":"T Yeh","year":"2007","unstructured":"Yeh T, Wu S, Lee C, Wen Z, Lee H, Yang Z et al. The short-term therapeutic effect of recombinant human bone morphogenetic protein-2 on collagenase-induced lumbar facet joint osteoarthritis in rats. Osteoarthritis Cartilage 2007; 15: 1357.","journal-title":"Osteoarthritis Cartilage"},{"key":"BFcddis2017208_CR3","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1053\/joca.1998.0129","volume":"6","author":"HM van Beuningen","year":"1998","unstructured":"van Beuningen HM, Glansbeek HL, van der Kraan PM, van den Berg WB . Differential effects of local application of BMP-2 or TGF-\u03b21 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage 1998; 6: 306\u2013317.","journal-title":"Osteoarthritis Cartilage"},{"key":"BFcddis2017208_CR4","doi-asserted-by":"publisher","first-page":"4065","DOI":"10.1002\/art.23034","volume":"56","author":"EN Blaney Davidson","year":"2007","unstructured":"Blaney Davidson EN, Vitters EL, van Beuningen HM, van de Loo FA, van den Berg WB, van der Kraan PM . Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation. Arthritis Rheum 2007; 56: 4065\u20134073.","journal-title":"Arthritis Rheum"},{"key":"BFcddis2017208_CR5","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1053\/joca.2000.0368","volume":"9","author":"AC Bakker","year":"2001","unstructured":"Bakker AC, van de Loo FA, van Beuningen HM, Sime P, van Lent PL, van der Kraan PM et al. Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage 2001; 9: 128\u2013136.","journal-title":"Osteoarthritis Cartilage"},{"key":"BFcddis2017208_CR6","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1053\/joca.1999.0267","volume":"8","author":"HM van Beuningen","year":"2000","unstructured":"van Beuningen HM, Glansbeek HL, van der Kraan PM, van den Berg WB . Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. Osteoarthritis Cartilage 2000; 8: 25\u201333.","journal-title":"Osteoarthritis Cartilage"},{"key":"BFcddis2017208_CR7","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1186\/s13075-014-0485-1","volume":"16","author":"S Grassel","year":"2014","unstructured":"Grassel S . The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther 2014; 16: 485.","journal-title":"Arthritis Res Ther"},{"key":"BFcddis2017208_CR8","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1177\/00220345930720030701","volume":"72","author":"MA Kido","year":"1993","unstructured":"Kido MA, Kiyoshima T, Kondo T, Ayasaka N, Moroi R, Terada Y et al. Distribution of substance P and calcitonin gene-related peptide-like immunoreactive nerve fibers in the rat temporomandibular joint. J Dental Res 1993; 72: 592\u2013598.","journal-title":"J Dental Res"},{"key":"BFcddis2017208_CR9","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1023\/A:1022099208535","volume":"14","author":"A Letic-Gavrilovic","year":"2003","unstructured":"Letic-Gavrilovic A, Piattelli A, Abe K . Nerve growth factor beta(NGF beta) delivery via a collagen\/hydroxyapatite (Col\/HAp) composite and its effects on new bone ingrowth. J Materials Sci Materials Med 2003; 14: 95\u2013102.","journal-title":"J Materials Sci Materials Med"},{"key":"BFcddis2017208_CR10","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1191\/0269215506cr954oa","volume":"20","author":"J Mehrholz","year":"2006","unstructured":"Mehrholz J, Rutte K, Pohl M . Jump training is feasible for nearly ambulatory patients after stroke. Clin Rehabil 2006; 20: 406\u2013412.","journal-title":"Clin Rehabil"},{"key":"BFcddis2017208_CR11","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1089\/ten.tea.2009.0384","volume":"16","author":"M Lee","year":"2010","unstructured":"Lee M, Siu RK, Ting K, Wu BM . Effect of Nell-1 delivery on chondrocyte proliferation and cartilaginous extracellular matrix deposition. Tissue Engineering Part A 2010; 16: 1791\u20131800.","journal-title":"Tissue Engineering Part A"},{"key":"BFcddis2017208_CR12","doi-asserted-by":"publisher","first-page":"E55","DOI":"10.1097\/SCS.0b013e3182418d02","volume":"23","author":"D Xiao","year":"2012","unstructured":"Xiao D, Hu J, Chen K, Man C, Zhu SS . Protection of articular cartilage by intra-articular injection of NEL-like molecule 1 in temporomandibular joint osteoarthritis. J Craniofac Surg 2012; 23: E55\u2013E58.","journal-title":"J Craniofac Surg"},{"key":"BFcddis2017208_CR13","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1002\/jbmr.314","volume":"26","author":"W Chen","year":"2011","unstructured":"Chen W, Zhang X, Siu RK, Chen F, Shen J, Zara JN et al. Nfatc2 is a primary response gene of nell\u20101 regulating chondrogenesis in ATDC5 cells. J Bone Mineral Res 2011; 26: 1230\u20131241.","journal-title":"J Bone Mineral Res"},{"key":"BFcddis2017208_CR14","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S0079-6123(03)46023-8","volume":"146","author":"K Kawamoto","year":"2004","unstructured":"Kawamoto K, Matsuda H . Nerve growth factor and wound healing. Progr Brain Res 2004; 146: 369.","journal-title":"Progr Brain Res"},{"key":"BFcddis2017208_CR15","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1096\/fj.01-1000fje","volume":"16","author":"G Cantarella","year":"2002","unstructured":"Cantarella G, Lempereur L, Presta M, Ribatti D, Lombardo G, Lazarovici P et al. Nerve growth factor\u2013endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J 2002; 16: 1307\u20131309.","journal-title":"FASEB J"},{"key":"BFcddis2017208_CR16","doi-asserted-by":"publisher","first-page":"3880","DOI":"10.1167\/iovs.12-10816","volume":"54","author":"T Blanco-Mezquita","year":"2013","unstructured":"Blanco-Mezquita T, Martinez-Garcia C, Proenca R, Zieske JD, Bonini S, Lambiase A et al. Nerve growth factor promotes corneal epithelial migration by enhancing expression of matrix metalloprotease-9. Invest Ophthalmol Visual Sci 2013; 54: 3880\u20133890.","journal-title":"Invest Ophthalmol Visual Sci"},{"key":"BFcddis2017208_CR17","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1055\/s-0032-1311633","volume":"44","author":"C Vera","year":"2012","unstructured":"Vera C, Tapia V, Kohan K, Gabler F, Ferreira A, Selman A et al. Nerve growth factor induces the expression of chaperone protein calreticulin in human epithelial ovarian cells. Hormone Metabolic Res 2012; 44: 639\u2013643.","journal-title":"Hormone Metabolic Res"},{"key":"BFcddis2017208_CR18","first-page":"981","volume":"13","author":"A Micera","year":"2007","unstructured":"Micera A, Lambiase A, Stampachiacchiere B, Sgrulletta R, Normando EM, Bonini S et al. Nerve growth factor has a modulatory role on human primary fibroblast cultures derived from vernal keratoconjunctivitis-affected conjunctiva. Mol Vision 2007; 13: 981.","journal-title":"Mol Vision"},{"key":"BFcddis2017208_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/exnr.1994.1037","volume":"126","author":"MH Tuszynski","year":"1994","unstructured":"Tuszynski MH, Peterson DA, Ray J, Baird A, Nakahara Y, Gage FH . Fibroblasts genetically modified to produce nerve growth factor induce robust neuritic ingrowth after grafting to the spinal cord. Exp Neurol 1994; 126: 1.","journal-title":"Exp Neurol"},{"key":"BFcddis2017208_CR20","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/0012-1606(88)90339-9","volume":"130","author":"M Kawamura","year":"1988","unstructured":"Kawamura M, Urist MR . Growth factors, mitogens, cytokines, and bone morphogenetic protein in induced chondrogenesis in tissue culture. Dev Biol 1988; 130: 435\u2013442.","journal-title":"Dev Biol"},{"key":"BFcddis2017208_CR21","doi-asserted-by":"publisher","first-page":"339","DOI":"10.4081\/844","volume":"47","author":"A Gigante","year":"2009","unstructured":"Gigante A, Bevilacqua C, Pagnotta A, Manzotti S, Toesca A, Greco F . Expression of NGF, Trka and p75 in human cartilage. Eur J Histochem 2009; 47: 339\u2013344.","journal-title":"Eur J Histochem"},{"key":"BFcddis2017208_CR22","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1093\/rheumatology\/41.12.1413","volume":"41","author":"F Iannone","year":"2002","unstructured":"Iannone F, De Bari C, Dell'Accio F, Covelli M, Patella V, Bianco GL et al. Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology 2002; 41: 1413\u20131418.","journal-title":"Rheumatology"},{"key":"BFcddis2017208_CR23","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1159\/000121432","volume":"188","author":"O Grimsholm","year":"2008","unstructured":"Grimsholm O, Guo Y, Ny T, Forsgren S . Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis. Cells Tissues Organs 2008; 188: 299\u2013309.","journal-title":"Cells Tissues Organs"},{"key":"BFcddis2017208_CR24","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1042\/CS20050163","volume":"110","author":"MV Chao","year":"2006","unstructured":"Chao MV, Rajagopal R, Lee FS . Neurotrophin signalling in health and disease. Clin Sci 2006; 110: 167\u2013173.","journal-title":"Clin Sci"},{"key":"BFcddis2017208_CR25","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1098\/rstb.2006.1894","volume":"361","author":"LF Reichardt","year":"2006","unstructured":"Reichardt LF . Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1545\u20131564.","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"BFcddis2017208_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1479-5876-10-239","volume":"10","author":"L Aloe","year":"2012","unstructured":"Aloe L, Rocco ML, Bianchi P, Manni L . Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 2012; 10: 1\u201315.","journal-title":"J Transl Med"},{"key":"BFcddis2017208_CR27","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.1038\/srep02683","volume":"3","author":"H-H Lee","year":"2013","unstructured":"Lee H-H, Chang C-C, Shieh M-J, Wang J-P, Chen Y-T, Young T-H et al. Hypoxia enhances chondrogenesis and prevents terminal differentiation through PI3K\/Akt\/FoxO dependent anti-apoptotic effect. Sci Rep-Uk 2013; 3: 2683.","journal-title":"Sci Rep-Uk"},{"key":"BFcddis2017208_CR28","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1677\/jme.1.02179","volume":"38","author":"S Ciarmatori","year":"2007","unstructured":"Ciarmatori S, Kiepe D, Haarmann A, Huegel U, T\u00f6nshoff B . Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3. 1C5. 18 in response to IGF-I. J Mol Endocrinol 2007; 38: 493\u2013508.","journal-title":"J Mol Endocrinol"},{"key":"BFcddis2017208_CR29","first-page":"18","volume":"10","author":"J Kilmon","year":"1992","unstructured":"Kilmon J . Snake venom:\" gentler\" purification provides attractive nerve growth factor source. Am Biotechnol Lab 1992; 10: 18 20.","journal-title":"Am Biotechnol Lab"},{"key":"BFcddis2017208_CR30","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.toxicon.2009.05.001","volume":"54","author":"V Paalme","year":"2009","unstructured":"Paalme V, Trummal K, Samel M, T\u00f5nism\u00e4gi K, J\u00e4rvek\u00fclg L, Vija H et al. Nerve growth factor from&lt; i&gt; Vipera lebetina&lt;\/i&gt; venom. Toxicon 2009; 54: 329\u2013336.","journal-title":"Toxicon"},{"key":"BFcddis2017208_CR31","doi-asserted-by":"publisher","first-page":"3811","DOI":"10.1096\/fj.12-207316","volume":"26","author":"Q Tong","year":"2012","unstructured":"Tong Q, Wang F, Zhou H-Z, Sun H-L, Song H, Shu Y-Y et al. Structural and functional insights into lipid-bound nerve growth factors. FASEB J 2012; 26: 3811\u20133821.","journal-title":"FASEB J"},{"key":"BFcddis2017208_CR32","first-page":"421","volume":"38","author":"L Chen","year":"2007","unstructured":"Chen L, Wang Y, Deng G, Yang L . Effect of NGF, which is isolated and purified from the venom of Naja naja atra, on expression of GAP-43 in dorsal root ganglia removed partially from cat. Sichuan da xue xue bao Yi xue ban J Sichuan Univ Med Sci Ed 2007; 38: 421\u2013423 455.","journal-title":"Sichuan da xue xue bao Yi xue ban J Sichuan Univ Med Sci Ed"},{"key":"BFcddis2017208_CR33","first-page":"359","volume":"8","author":"XB Li","year":"1999","unstructured":"Li XB, Chen MJ, Lei DQ, Yang B, Liao GS, Shu YY et al. Bioactivities of nerve growth factor from Chinese cobra venom. J Natural Toxins 1999; 8: 359\u2013362.","journal-title":"J Natural Toxins"},{"key":"BFcddis2017208_CR34","first-page":"73","volume":"9","author":"XB Li","year":"2000","unstructured":"Li XB, Liao GS, Shu YY, Tang SX . Brain delivery of biotinylated NGF bounded to an avidin-transferrin conjugate. J Natural Toxins 2000; 9: 73\u201383.","journal-title":"J Natural Toxins"},{"key":"BFcddis2017208_CR35","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.jchromb.2004.02.030","volume":"805","author":"L-j Bian","year":"2004","unstructured":"Bian L-j, Wu P, Yang X-y . Two-step chromatographic method for separation and purification of nerve growth factor from venom of Chinese cobra. J Chromatogr B 2004; 805: 119\u2013125.","journal-title":"J Chromatogr B"},{"key":"BFcddis2017208_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0003-2697(80)90229-8","volume":"103","author":"FE Regnier","year":"1980","unstructured":"Regnier FE, Gooding KM . High-performance liquid chromatography of proteins. Anal Biochem 1980; 103: 1\u201325.","journal-title":"Anal Biochem"},{"key":"BFcddis2017208_CR37","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/0003-2697(86)90239-3","volume":"155","author":"GB Irvine","year":"1986","unstructured":"Irvine GB, Shaw C . High-performance gel permeation chromatography of proteins and peptides on columns of TSK-G2000-SW and TSK-G3000-SW: a volatile solvent giving separation based on charge and size of polypeptides. Anal Biochem 1986; 155: 141\u2013148.","journal-title":"Anal Biochem"},{"key":"BFcddis2017208_CR38","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.biomaterials.2014.10.049","volume":"39","author":"P Chen","year":"2015","unstructured":"Chen P, Tao J, Zhu S, Cai Y, Mao Q, Yu D et al. Radially oriented collagen scaffold with SDF-1 promotes osteochondral repair by facilitating cell homing. Biomaterials 2015; 39: 114\u2013123.","journal-title":"Biomaterials"},{"key":"BFcddis2017208_CR39","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.biomaterials.2012.10.027","volume":"34","author":"W Zhang","year":"2013","unstructured":"Zhang W, Chen J, Tao J, Jiang Y, Hu C, Huang L et al. The use of type 1 collagen scaffold containing stromal cell-derived factor-1 to create a matrix environment conducive to partial-thickness cartilage defects repair. Biomaterials 2013; 34: 713\u2013723.","journal-title":"Biomaterials"},{"key":"BFcddis2017208_CR40","doi-asserted-by":"publisher","first-page":"4983","DOI":"10.1016\/j.actbio.2014.08.022","volume":"10","author":"W Wang","year":"2014","unstructured":"Wang W, Sun L, Zhang P, Song J, Liu W . An anti-inflammatory cell-free collagen\/resveratrol scaffold for repairing osteochondral defects in rabbits. Acta Biomater 2014; 10: 4983\u20134995.","journal-title":"Acta Biomater"},{"key":"BFcddis2017208_CR41","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jbm.a.32588","volume":"93","author":"L Zheng","year":"2010","unstructured":"Zheng L, Fan HS, Sun J, Chen XN, Wang G, Zhang L et al. Chondrogenic differentiation of mesenchymal stem cells induced by collagen-based hydrogel: an in vivo study. J Biomed Materials Res Pt A 2010; 93: 783\u2013792.","journal-title":"J Biomed Materials Res Pt A"},{"key":"BFcddis2017208_CR42","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1089\/ten.tea.2014.0375","volume":"21","author":"P Smeriglio","year":"2014","unstructured":"Smeriglio P, Dhulipala L, Lai JH, Goodman SB, Dragoo JL, Smith RL et al. Collagen VI enhances cartilage tissue generation by stimulating chondrocyte proliferation. Tissue Engineering Pt A 2014; 21: 840\u2013849.","journal-title":"Tissue Engineering Pt A"},{"key":"BFcddis2017208_CR43","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1089\/ten.tea.2012.0233","volume":"19","author":"CSD Lee","year":"2013","unstructured":"Lee CSD, Watkins E, Burnsed OA, Schwartz Z, Boyan BD . Tailoring adipose stem cell trophic factor production with differentiation medium components to regenerate chondral defects. Tissue Engineering Pt A 2013; 19: 1451\u20131464.","journal-title":"Tissue Engineering Pt A"},{"key":"BFcddis2017208_CR44","doi-asserted-by":"publisher","first-page":"S36","DOI":"10.1053\/joca.2001.0442","volume":"9","author":"M Mastrogiacomo","year":"2001","unstructured":"Mastrogiacomo M, Cancedda R, Quarto R . Effect of different growth factors on the chondrogenic potential of human bone marrow stromal cells. Osteoarthritis Cartilage 2001; 9: S36\u2013S40.","journal-title":"Osteoarthritis Cartilage"},{"key":"BFcddis2017208_CR45","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1634\/stemcells.2004-0062","volume":"22","author":"BC Heng","year":"2004","unstructured":"Heng BC, Cao T, Lee EH . Directing stem cell differentiation into the chondrogenic lineage in vitro. Stem Cells 2004; 22: 1152\u20131167.","journal-title":"Stem Cells"},{"key":"BFcddis2017208_CR46","first-page":"183","volume":"149","author":"V Colafrancesco","year":"2011","unstructured":"Colafrancesco V, Villoslada P, Targeting NGF . pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases. Arch Italiennes de Biologie 2011; 149: 183\u2013192.","journal-title":"Arch Italiennes de Biologie"},{"key":"BFcddis2017208_CR47","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1002\/jnr.22535","volume":"89","author":"J Ding","year":"2011","unstructured":"Ding J, Cheng Y, Gao S, Chen J . Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res 2011; 89: 222\u2013230.","journal-title":"J Neurosci Res"},{"key":"BFcddis2017208_CR48","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s11010-013-1768-6","volume":"383","author":"J Yuan","year":"2013","unstructured":"Yuan J, Huang GR, Xiao Z, Lin LB, Han TW . Overexpression of beta-NGF promotes differentiation of bone marrow mesenchymal stem cells into neurons through regulation of AKT and MAPK pathway. Mol Cell Biochem 2013; 383: 201\u2013211.","journal-title":"Mol Cell Biochem"},{"key":"BFcddis2017208_CR49","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1002\/cbin.10217","volume":"38","author":"HB Zhao","year":"2014","unstructured":"Zhao HB, Ma H, Ha XQ, Zheng P, Li XY, Zhang M et al. Salidroside induces rat mesenchymal stem cells to differentiate into dopaminergic neurons. Cell Biol Int 2014; 38: 462\u2013471.","journal-title":"Cell Biol Int"},{"key":"BFcddis2017208_CR50","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1038\/aps.2011.141","volume":"32","author":"WX Wang","year":"2011","unstructured":"Wang WX, Hu XY, Xie XJ, Liu XB, Wu RR, Wang YP et al. Nerve growth factor induces cord formation of mesenchymal stem cell by promoting proliferation and activating the PI3K\/Akt signaling pathway. Acta Pharmacol Sin 2011; 32: 1483\u20131490.","journal-title":"Acta Pharmacol Sin"},{"key":"BFcddis2017208_CR51","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.1038\/srep02683","volume":"3","author":"HH Lee","year":"2013","unstructured":"Lee HH, Chang CC, Shieh MJ, Wang JP, Chen YT, Young TH et al. Hypoxia enhances chondrogenesis and prevents terminal differentiation through PI3K\/Akt\/FoxO dependent anti-apoptotic effect. Sci Rep-Uk 2013; 3: 2683.","journal-title":"Sci Rep-Uk"},{"key":"BFcddis2017208_CR52","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1111\/j.1365-2443.2008.01209.x","volume":"13","author":"K Kita","year":"2008","unstructured":"Kita K, Kimura T, Nakamura N, Yoshikawa H, Nakano T . PI3K\/Akt signaling as a key regulatory pathway for chondrocyte terminal differentiation. Genes Cells 2008; 13: 839\u2013850.","journal-title":"Genes Cells"},{"key":"BFcddis2017208_CR53","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.scr.2015.02.006","volume":"14","author":"Y-H Zhao","year":"2015","unstructured":"Zhao Y-H, Lv X, Liu Y-L, Zhao Y, Li Q, Chen Y-J et al. Hydrostatic pressure promotes the proliferation and osteogenic\/chondrogenic differentiation of mesenchymal stem cells: the roles of RhoA and Rac1. Stem Cell Res 2015; 14: 283\u2013296.","journal-title":"Stem Cell Res"},{"key":"BFcddis2017208_CR54","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1007\/s00441-014-2010-x","volume":"358","author":"Y Zhang","year":"2014","unstructured":"Zhang Y, Pizzute T, Pei M . A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration. Cell Tissue Res 2014; 358: 633\u2013649.","journal-title":"Cell Tissue Res"},{"key":"BFcddis2017208_CR55","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.bbrc.2008.01.160","volume":"368","author":"LA McMahon","year":"2008","unstructured":"McMahon LA, Prendergast PJ, Campbell VA . A comparison of the involvement of p38, ERK1\/2 and PI3K in growth factor-induced chondrogenic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun 2008; 368: 990\u2013995.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFcddis2017208_CR56","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/jor.22892","volume":"33","author":"AE Rapp","year":"2015","unstructured":"Rapp AE, Kroner J, Baur S, Schmid F, Walmsley A, Mottl H et al. Analgesia via blockade of NGF\/TrkA signaling does not influence fracture healing in mice. J Orthop Res 2015; 33: 1235\u20131241.","journal-title":"J Orthop Res"},{"key":"BFcddis2017208_CR57","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1083\/jcb.130.1.149","volume":"130","author":"MD Ehlers","year":"1995","unstructured":"Ehlers MD, Kaplan DR, Price DL, Koliatsos VE . NGF-stimulated retrograde transport of trkA in the mammalian nervous system. J Cell Biol 1995; 130: 149\u2013156.","journal-title":"J Cell Biol"},{"key":"BFcddis2017208_CR58","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1006\/mcne.1999.0770","volume":"14","author":"M Hamanoue","year":"1999","unstructured":"Hamanoue M, Middleton G, Wyatt S, Jaffray E, Hay RT, Davies AM . p75-mediated NF-\u03baB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol Cell Neurosci 1999; 14: 28\u201340.","journal-title":"Mol Cell Neurosci"},{"key":"BFcddis2017208_CR59","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1089\/ten.tea.2008.0268","volume":"15","author":"L Zheng","year":"2009","unstructured":"Zheng L, Sun J, Chen X, Wang G, Jiang B, Fan H et al. In vivo cartilage engineering with collagen hydrogel and allogenous chondrocytes after diffusion chamber implantation in immunocompetent host. Tissue Engineering Pt A 2009; 15: 2145\u20132153.","journal-title":"Tissue Engineering Pt A"},{"key":"BFcddis2017208_CR60","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jbm.a.32588","volume":"93","author":"L Zheng","year":"2010","unstructured":"Zheng L, Fan H, Sun J, Chen X, Wang G, Zhang L et al. Chondrogenic differentiation of mesenchymal stem cells induced by collagen\u2010based hydrogel: an in vivo study. J Biomed Materials Res Pt A 2010; 93: 783\u2013792.","journal-title":"J Biomed Materials Res Pt A"},{"key":"BFcddis2017208_CR61","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1089\/ten.tea.2009.0681","volume":"16","author":"Y Jiang","year":"2010","unstructured":"Jiang Y, Chen LK, Zhu DC, Zhang GR, Guo C, Qi YY et al. The inductive effect of bone morphogenetic protein-4 on chondral-lineage differentiation and in situ cartilage repair. Tissue Engineering Pt A 2010; 16: 1621\u20131632.","journal-title":"Tissue Engineering Pt A"},{"key":"BFcddis2017208_CR62","doi-asserted-by":"publisher","first-page":"579","DOI":"10.2106\/00004623-199404000-00013","volume":"76","author":"S Wakitani","year":"1994","unstructured":"Wakitani S, Goto T, Pineda SJ, Young RG, Mansour JM, Caplan AI et al. Mesenchymal cell-based repair of large, full-thickness defects of articulsar cartilage. J Bone Joint Surg Am 1994; 76: 579\u2013592.","journal-title":"J Bone Joint Surg Am"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2017208.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017208","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/cddis.2017.208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017208.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T06:03:36Z","timestamp":1719209016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2017208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,18]]},"references-count":62,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["BFcddis2017208"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2017.208","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,18]]},"assertion":[{"value":"24 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2017","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}