{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T03:39:37Z","timestamp":1789270777235,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["21H03108"],"award-info":[{"award-number":["21H03108"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["20H03808"],"award-info":[{"award-number":["20H03808"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The nuclear factor-\u03baB (NF-\u03baB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50\/p105 (NF-\u03baB1), and p52\/p100 (NF-\u03baB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-\u03baB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-1\u03b2, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-\u03baB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-\u03baB is required for osteoclast differentiation. The NF-\u03baB signaling pathway is controlled by various regulators, including NF-\u03baB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-\u03baB signaling molecules that have been identified in patients with osteopetrosis.<\/jats:p>","DOI":"10.3390\/ijms23147995","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T11:22:24Z","timestamp":1658316144000},"page":"7995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Critical Roles of NF-\u03baB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-5299","authenticated-orcid":false,"given":"Eijiro","family":"Jimi","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan"},{"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9304-2098","authenticated-orcid":false,"given":"Takenobu","family":"Katagiri","sequence":"additional","affiliation":[{"name":"Research Center for Genomic Medicine, Division of Biomedical Sciences, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.mpmed.2013.07.007","article-title":"Bone structure and metabolism","volume":"41","author":"Ralston","year":"2013","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jht.2011.08.003","article-title":"Specialized connective tissue: Bone, the structural framework of the upper extremity","volume":"25","author":"Weatherholt","year":"2012","journal-title":"J. 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