{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:59:51Z","timestamp":1791644391333,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:00:00Z","timestamp":1576108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid from the Research Fellowship for Young Scientists","award":["JP16J09963"],"award-info":[{"award-number":["JP16J09963"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The nuclear factor-\u03baB (NF-\u03baB) is a transcription factor that regulates the expression of genes that control cell proliferation and apoptosis, as well as genes that respond to inflammation and immune responses. There are two means of NF-\u03baB activation: the classical pathway, which involves the degradation of the inhibitor of \u03baB\u03b1 (I\u03baB\u03b1), and the alternative pathway, which involves the NF-\u03baB-inducing kinase (NIK, also known as MAP3K14). The mouse growth plate consists of the resting zone, proliferative zone, prehypertrophic zone, and hypertrophic zone. The p65 (RelA), which plays a central role in the classical pathway, is expressed throughout the cartilage layer, from the resting zone to the hypertrophic zone. Inhibiting the classical NF-\u03baB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis. Since the production of autoantibodies and inflammatory cytokines, such as tumor necrosis factor-\u03b1 (TNF\u03b1), interleukin (IL)-1\u03b2, IL-6, and IL-17, are regulated by the classical pathways and are increased in rheumatoid arthritis (RA), NF-\u03baB inhibitors are used to suppress inflammation and joint destruction in RA models. In osteoarthritis (OA) models, the strength of NF-\u03baB-activation is found to regulate the facilitation or suppression of OA. On the other hand, RelB is involved in the alternative pathway, and is expressed in the periarticular zone during the embryonic period of development. The alternative pathway is involved in the generation of chondrocytes in the proliferative zone during physiological conditions, and in the development of RA and OA during pathological conditions. Thus, NF-\u03baB is an important molecule that controls normal development and the pathological destruction of cartilage.<\/jats:p>","DOI":"10.3390\/ijms20246275","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T11:06:41Z","timestamp":1576148801000},"page":"6275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":298,"title":["NF-\u03baB Signaling Regulates Physiological and Pathological Chondrogenesis"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-5299","authenticated-orcid":false,"given":"Eijiro","family":"Jimi","sequence":"first","affiliation":[{"name":"Oral Health\/Brain Health\/Total Health Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"name":"Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Huang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Nakatomi","sequence":"additional","affiliation":[{"name":"Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a008334","DOI":"10.1101\/cshperspect.a008334","article-title":"Development of the endochondral skeleton","volume":"5","author":"Long","year":"2013","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.11005\/jbm.2017.24.2.75","article-title":"Transcriptional network controlling endochondral ossification","volume":"24","author":"Hata","year":"2017","journal-title":"J. Bone Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1101\/gad.845101","article-title":"Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice","volume":"15","author":"Takeda","year":"2001","journal-title":"Genes Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.0105-2896.2005.00329.x","article-title":"Role of nuclear factor-\u03baB in the immune system and bone","volume":"208","author":"Jimi","year":"2005","journal-title":"Immunol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.smim.2014.05.004","article-title":"Regulation of NF-\u03baB by TNF family cytokines","volume":"26","author":"Hayden","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_7","first-page":"720","article-title":"Role of Nuclear Factor-\u03baB (NF-\u03baB) in growth plate chondrogenesis","volume":"13","year":"2016","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/cr.2010.159","article-title":"Role of NF-\u03baB in the skeleton","volume":"21","author":"Novack","year":"2011","journal-title":"Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"33698","DOI":"10.1074\/jbc.M702991200","article-title":"Nuclear factor-\u03baB p65 facilitates longitudinal bone growth by inducing growth plate chondrocyteproliferation and differentiation and by preventing apoptosis","volume":"282","author":"Wu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13336","DOI":"10.1038\/ncomms13336","article-title":"Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_12","first-page":"a001651","article-title":"The nuclear factor NF-\u03baB pathway in inflammation","volume":"6","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cytogfr.2008.11.007","article-title":"NF-\u03baB modulators in osteolytic bone diseases","volume":"20","author":"Xu","year":"2009","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.bbrc.2007.10.200","article-title":"In vitro selection of optimal RelB\/p52 DNA-binding motifs","volume":"365","author":"Britanova","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/33429","article-title":"Role of Rel\/NF-\u03baB transcription factors during the outgrowth of the vertebrate limb","volume":"392","author":"Kanegae","year":"1998","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34037","DOI":"10.1074\/jbc.M803754200","article-title":"Stimulatory effects of insulin-like growth factor-I on growth plate chondrogenesis are mediated by nuclear factor-\u03baB p65","volume":"283","author":"Wu","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24726","DOI":"10.1074\/jbc.M110.175364","article-title":"Nuclear factor-\u03baB (NF-\u03baB) p65 interacts with Stat5b in growth plate chondrocytes and mediates the effects of growth hormone on chondrogenesis and on the expression of insulin-like growth factor-1 and bone morphogenetic protein-2","volume":"286","author":"Wu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29130","DOI":"10.1074\/jbc.M212296200","article-title":"NF-\u03baB specifically activates BMP-2 gene expression in growth plate chondrocytes in vivo and in a chondrocyte cell line in vitro","volume":"278","author":"Feng","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/nm1197-1285","article-title":"Osteopetrosis in mice lacking NF-\u03baB1 and NF-\u03baB2","volume":"3","author":"Iotsova","year":"1997","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1101\/gad.11.24.3482","article-title":"Requirement for NF-\u03baB in osteoclast and B-cell development","volume":"11","author":"Franzoso","year":"1997","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Caron, M.M., Emans, P.J., Surtel, D.A., Cremers, A., Voncken, J.W., Welting, T.J., and van Rhijn, L.W. (2012). Activation of NF-\u03baB\/p65 facilitates early chondrogenic differentiation during endochondral ossification. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033467"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1210\/en.2014-1983","article-title":"Insulin-like growth factor-independent effects of growth hormone on growth plate chondrogenesis and longitudinal bone growth","volume":"156","author":"Wu","year":"2015","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1126\/science.284.5412.313","article-title":"Limb and skin abnormalities in mice lacking IKK\u03b1","volume":"284","author":"Takeda","year":"1999","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1101\/gad.13.10.1322","article-title":"IKK1-deficient mice exhibit abnormal development of skin and skeleton","volume":"13","author":"Li","year":"1999","journal-title":"Genes Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bone.2019.01.002","article-title":"Constitutive activation of the alternative NF-\u03baB pathway disturbs endochondral ossification","volume":"121","author":"Nakatomi","year":"2019","journal-title":"Bone"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1084\/jem.186.7.999","article-title":"Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-\u03baB2","volume":"186","author":"Ishikawa","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1093\/rheumatology\/kem298","article-title":"Signalling, inflammation and arthritis: NF-\u03baB and its relevance to arthritis and inflammation","volume":"47","author":"Simmonds","year":"2008","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri.2017.52","article-title":"The non-canonical NF-\u03baB pathway in immunity and inflammation","volume":"17","author":"Sun","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","first-page":"827","article-title":"High DNA-binding activity of transcription factor NF-\u03baB in synovial membranes of patients with rheumatoid arthritis","volume":"37","author":"Asahara","year":"1995","journal-title":"Biochem. Mol. Biol. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"518S","DOI":"10.1042\/bst025518s","article-title":"NF-\u03baB activation in human knee-joint synovial tissue during the early stage of joint inflammation","volume":"25","author":"Gilston","year":"1997","journal-title":"Biochem. Soc. Trans."},{"key":"ref_31","first-page":"793","article-title":"Constitutive transcription of the human interleukin-6 gene by rheumatoid synoviocytes: Spontaneous activation of NF-\u03baB and CBF1","volume":"152","author":"Miyazawa","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3109\/08916939808995367","article-title":"AP-1 and NF-\u03baB regulation in rheumatoid arthritis and murine collagen-induced arthritis","volume":"28","author":"Han","year":"1998","journal-title":"Autoimmunity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13859","DOI":"10.1073\/pnas.95.23.13859","article-title":"NF-\u03baB activation provides the potential link between inflammation and hyperplasia in the arthritic joint","volume":"95","author":"Miagkov","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15671","DOI":"10.1073\/pnas.95.26.15671","article-title":"Role of the proteasome and NF-\u03baB in streptococcal cell wall-induced polyarthritis","volume":"95","author":"Palombella","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1002\/1529-0131(200108)44:8<1897::AID-ART328>3.0.CO;2-4","article-title":"Inhibitor of nuclear factor \u03baB kinase beta is a key regulator of synovial inflammation","volume":"44","author":"Tak","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1084\/jem.20042081","article-title":"I\u03baB kinase (IKK)\u03b2, but not IKK\u03b1, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss","volume":"201","author":"Ruocco","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nm1054","article-title":"Selective inhibition of NF-\u03baB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo","volume":"10","author":"Jimi","year":"2004","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"37219","DOI":"10.1074\/jbc.C400258200","article-title":"The I\u03baB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis","volume":"279","author":"Dai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.4049\/jimmunol.171.10.5547","article-title":"Direct inhibition of NF-\u03baB blocks bone erosion associated with inflammatory arthritis","volume":"171","author":"Clohisy","year":"2003","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1002\/art.11131","article-title":"A highly selective inhibitor of I\u03baB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice","volume":"48","author":"McIntyre","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-0-387-72009-8_16","article-title":"Control of osteoclast activity and bone loss by IKK subunits: New targets for therapy","volume":"602","author":"Ruocco","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.3899\/jrheum.150245","article-title":"Nuclear Factor-\u03baB-inducing Kinase Is Expressed in Synovial Endothelial Cells in Patients with Early Arthritis and Correlates with Markers of Inflammation: A Prospective Cohort Study","volume":"42","author":"Maijer","year":"2015","journal-title":"J. Rheumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/path.4403","article-title":"NF-\u03baB-inducing kinase is a key regulator of inflammation-induced and tumour-associated angiogenesis","volume":"234","author":"Noort","year":"2014","journal-title":"J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1172\/JCI23763","article-title":"NF-\u03baB-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis","volume":"115","author":"Aya","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yang, C., McCoy, K., Davis, J.L., Schmidt-Supprian, M., Sasaki, Y., Faccio, R., and Novack, D.V. (2010). NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015383"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S","article-title":"Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases","volume":"44","author":"Cheema","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6","DOI":"10.4049\/jimmunol.166.1.6","article-title":"Cutting edge: A role for B lymphocyte stimulator in systemic lupus erythematosus","volume":"166","author":"Zhang","year":"2001","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/89782","article-title":"TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice","volume":"2","author":"Wang","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0140-6736(01)06006-8","article-title":"Risk factors for progression of knee osteoarthritis","volume":"358","author":"Doherty","year":"2001","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fbioe.2018.00018","article-title":"Recent Insights into the contribution of the changing hypertrophic chondrocyte phenotype in the development and progression of osteoarthritis","volume":"6","author":"Ripmeester","year":"2018","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1002\/art.1780381209","article-title":"Nuclear factor-\u03baB in rheumatoid synovium. Localization of p50 and p65","volume":"38","author":"Handel","year":"1995","journal-title":"Arthritis Rheum."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/art.23211","article-title":"Differential requirements for IKK\u03b1 and IKK\u03b2 in the differentiation of primary human osteoarthritic chondrocytes","volume":"58","author":"Olivotto","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13075-017-1296-y","article-title":"Molecular mechanisms underlying osteoarthritis development: Notch and NF-\u03baB","volume":"19","author":"Saito","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16475","DOI":"10.1038\/s41598-018-34830-9","article-title":"Intra-articular administration of I\u03baB\u03b1 kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-\u03baB\/HIF-2\u03b1 axis","volume":"8","author":"Murahashi","year":"2018","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:41:49Z","timestamp":1760190109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/24\/6275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,12]]},"references-count":54,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20246275"],"URL":"https:\/\/doi.org\/10.3390\/ijms20246275","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,12]]}}}