{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T01:03:49Z","timestamp":1792717429231,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T00:00:00Z","timestamp":1571184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The deleterious effects of nicotine on various health conditions have been well documented. Although many orthopedic diseases are adversely affected by nicotine, little is known about its preclinical effects on chondrogenesis or osteogenesis, cartilage formation, osteoarthritis (OA), and osteochondral repair. A systematic review was conducted examining the current scientific evidence on the effects of nicotine on chondrogenesis or osteogenesis in vitro, possible consequences of prenatal nicotine exposure (PNE) on cartilage and OA susceptibility in the offspring, and whether nicotine affects OA development and osteochondral repair in vivo, always focusing on their underlying mechanisms. The data reveal dose-dependent effects on articular chondrocytes and on the chondrogenesis and osteogenesis of medicinal signaling cells in vitro, with lower doses often resulting in positive effects and higher doses causing negative effects. PNE negatively affects articular cartilage development and induces OA in the offspring without or with nicotine exposure. In contrast, protective effects on OA development were only reported in monosodium iodoacetate-induced small animal models. Finally, nicotine repressed MSC-based osteochondral repair in vivo. Future studies need to investigate dose-dependent clinical effects of smoking on cartilage quality in offspring, OA susceptibility and progression, and osteochondral repair more in detail, thus identifying possible thresholds for its pathological effects.<\/jats:p>","DOI":"10.3390\/jcm8101699","type":"journal-article","created":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T04:46:06Z","timestamp":1571287566000},"page":"1699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Association of Nicotine with Osteochondrogenesis and Osteoarthritis Development: The State of the Art of Preclinical Research"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1547-0764","authenticated-orcid":false,"given":"Xiaoyu","family":"Cai","sequence":"first","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1438-9670","authenticated-orcid":false,"given":"Liang","family":"Gao","sequence":"additional","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0323-8922","authenticated-orcid":false,"given":"Magali","family":"Cucchiarini","sequence":"additional","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8612-4842","authenticated-orcid":false,"given":"Henning","family":"Madry","sequence":"additional","affiliation":[{"name":"Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg\/Saar, Germany"},{"name":"Department of Orthopaedic Surgery, Saarland University Medical Center and Saarland University, 66421 Homburg\/Saar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.joca.2014.12.011","article-title":"An educational review of cartilage repair: precepts & practice-myths & misconceptions--progress & prospects","volume":"23","author":"Hunziker","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41584-018-0125-2","article-title":"Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair","volume":"15","author":"Cucchiarini","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.joca.2018.10.004","article-title":"Osteoarthritis year in review 2018: Genetics and epigenetics","volume":"27","author":"Jeffries","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.joca.2018.12.011","article-title":"Osteoarthritis year in review 2018: mechanics","volume":"27","author":"DeFrate","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liu, Y., Zhang, H., Liang, N., Fan, W., Li, J., Huang, Z., Yin, Z., Wu, Z., and Hu, J. (2016). Prevalence and associated factors of knee osteoarthritis in a rural Chinese adult population: an epidemiological survey. BMC Public Health, 16.","DOI":"10.1186\/s12889-016-2782-x"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.joca.2007.03.004","article-title":"Which relationship does osteoarthritis share with smoking?","volume":"15","author":"Elloumi","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11010-011-1020-1","article-title":"Nicotine promotes proliferation and collagen synthesis of chondrocytes isolated from normal human and osteoarthritis patients","volume":"359","author":"Ying","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1055\/s-0030-1270894","article-title":"Factors that influence clinical outcome following autologous chondrocyte implantation for cartilage defects of the knee","volume":"150","author":"Niemeyer","year":"2012","journal-title":"Z. Fur Orthop. Und Unf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13287-018-0853-x","article-title":"Histone hypo-acetylation of Sox9 mediates nicotine-induced weak cartilage repair by suppressing BMSC chondrogenic differentiation","volume":"9","author":"Tie","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5435\/00124635-200101000-00002","article-title":"The musculoskeletal effects of smoking","volume":"9","author":"Porter","year":"2001","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"337","DOI":"10.4184\/asj.2017.11.3.337","article-title":"The Clinical Correlations between Diabetes, Cigarette Smoking and Obesity on Intervertebral Degenerative Disc Disease of the Lumbar Spine","volume":"11","author":"Jakoi","year":"2017","journal-title":"Asian Spine J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1159\/000369724","article-title":"Activation of alpha7 nicotinic acetylcholine receptors prevents monosodium iodoacetate-induced osteoarthritis in rats","volume":"35","author":"Liu","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/art.22591","article-title":"Smoking interacts with family history with regard to change in knee cartilage volume and cartilage defect development","volume":"56","author":"Ding","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.joca.2014.11.022","article-title":"Smoking and osteoarthritis: A review of the evidence and its implications","volume":"23","author":"Felson","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"485","DOI":"10.4049\/jimmunol.1801513","article-title":"Nicotine Attenuates Osteoarthritis Pain and Matrix Metalloproteinase-9 Expression via the alpha7 Nicotinic Acetylcholine Receptor","volume":"203","author":"Teng","year":"2019","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1136\/ard.58.3.151","article-title":"Osteoarthrosis of the knee in men and women in association with overweight, smoking, and hormone therapy","volume":"58","author":"Sandmark","year":"1999","journal-title":"Ann. Rheum. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1096\/fj.15-274399","article-title":"Intrauterine low-functional programming of IGF1 by prenatal nicotine exposure mediates the susceptibility to osteoarthritis in female adult rat offspring","volume":"30","author":"Tie","year":"2016","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/sctm.17-0051","article-title":"Mesenchymal Stem Cells: Time to Change the Name!","volume":"6","author":"Caplan","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22957","DOI":"10.1038\/srep22957","article-title":"Acute stimulation of mesenchymal stem cells with cigarette smoke extract affects their migration, differentiation, and paracrine potential","volume":"6","author":"Wahl","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1089\/scd.2012.0434","article-title":"Nicotine alters MicroRNA expression and hinders human adult stem cell regenerative potential","volume":"22","author":"Ng","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7828","DOI":"10.1038\/srep07828","article-title":"Cigarette smoking hinders human periodontal ligament-derived stem cell proliferation, migration and differentiation potentials","volume":"5","author":"Ng","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1007\/s00167-012-1890-0","article-title":"Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro","volume":"20","author":"Ying","year":"2012","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3233\/BME-2012-0692","article-title":"Effect of nicotine on chondrogenic differentiation of rat bone marrow mesenchymal stem cells in alginate bead culture","volume":"22","author":"Deng","year":"2012","journal-title":"Bio-Med. Mater. Eng."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S217","DOI":"10.3233\/BME-171644","article-title":"Effect of nicotine on the proliferation and chondrogenic differentiation of the human Wharton\u2019s jelly mesenchymal stem cells","volume":"28","author":"Yang","year":"2017","journal-title":"Bio-Med. Mater. Eng."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14281","DOI":"10.1038\/s41598-017-14634-z","article-title":"Electronic Cigarette Smoke Impairs Normal Mesenchymal Stem Cell Differentiation","volume":"7","author":"Shaito","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/0003-9969(95)00022-H","article-title":"The effects of smokeless tobacco extract on bone nodule formation and mineralization by chick osteoblasts in vitro","volume":"40","author":"Henderson","year":"1995","journal-title":"Arch. Oral Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3181\/00379727-199-43349","article-title":"Inhibition of cell metabolism by a smokeless tobacco extract: Tissue and species specificity","volume":"199","author":"Lenz","year":"1992","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.taap.2018.03.018","article-title":"Prenatal nicotine exposure intergenerationally programs imperfect articular cartilage via histone deacetylation through maternal lineage","volume":"352","author":"Xie","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.reprotox.2015.12.010","article-title":"Prenatal nicotine exposure induces poor articular cartilage quality in female adult offspring fed a high-fat diet and the intrauterine programming mechanisms","volume":"60","author":"Tie","year":"2016","journal-title":"Reprod. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_31","first-page":"2973","article-title":"Fundamental carcinogenic processes and their implications for low dose risk assessment","volume":"36","author":"Crump","year":"1976","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/02791072.2010.10400689","article-title":"Buprenorphine in the treatment of opiate dependence","volume":"42","author":"Wesson","year":"2010","journal-title":"J. Psychoact. Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kawakita, A., Sato, K., Makino, H., Ikegami, H., Takayama, S., Toyama, Y., and Umezawa, A. (2008). Nicotine acts on growth plate chondrocytes to delay skeletal growth through the alpha7 neuronal nicotinic acetylcholine receptor. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003945"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2165\/00003088-200140090-00003","article-title":"The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments","volume":"40","author":"Schneider","year":"2001","journal-title":"Clin. Pharmacokinet."},{"key":"ref_35","first-page":"797","article-title":"Maternal Smoking During Pregnancy Is Associated With Offspring\u2019s Musculoskeletal Pain in Adolescence: Structural Equation Modeling","volume":"19","author":"Maatta","year":"2017","journal-title":"Nicotine Tob. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gao, L., Goebel, L.K.H., Orth, P., Cucchiarini, M., and Madry, H. (2018). Subchondral drilling for articular cartilage repair: A systematic review of translational research. Dis. Models Mech., 11.","DOI":"10.1242\/dmm.034280"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1609685","DOI":"10.1155\/2017\/1609685","article-title":"Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects","volume":"2017","author":"Madry","year":"2017","journal-title":"Stem Cells Int."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1699\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:55Z","timestamp":1760189215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,16]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["jcm8101699"],"URL":"https:\/\/doi.org\/10.3390\/jcm8101699","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,16]]}}}