{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough none of the provided studies directly mention MIR4666A, the collection of abstracts largely characterizes the function of an interferon‐induced transmembrane protein—the osteoblast‐specific IFITM5 (also known as BRIL)—which may help illuminate how related regulatory RNAs (such as MIR4666A, if co‐expressed or functionally linked) could influence bone formation. In one study focusing on chemical communication in mammals, a novel secreted peptide was identified from exocrine glands that modulated sensory neurons via the vomeronasal organ, underscoring the broader diversity of secreted signals in mammals (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " \n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe majority of the research, however, centers on IFITM5’s key role in osteoblast differentiation and bone mineralization. IFITM5/BRIL is expressed in early mineralization stages, promotes the differentiation of osteoblasts, and has been shown to interact directly with proteins such as FKBP11—interactions that are critical for subsequent immune-related gene induction in bone cells (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " \n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther investigations have revealed that IFITM5 participates in forming multiprotein complexes at the plasma membrane and that post‐translational modifications, particularly S‐palmitoylation, are essential for its proper interaction with FKBP11, thereby influencing bone nodule formation and proper osteoblast function. This modification ensures appropriate subcellular localization and functional coupling to downstream signaling pathways that drive not only mineralization but also modulate immune system activity in bone (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in IFITM5 have been directly implicated in the pathogenesis of osteogenesis imperfecta type V—a disorder characterized by bone fragility, deformities, and impaired mineralization. Transgenic and conditional mouse models have elucidated that the mutant form of IFITM5 causes aberrant skeletal development, including delayed mineralization, abnormal growth plates, and disrupted differentiation of skeletal progenitors, underscoring a neomorphic (gain‐of‐function) mechanism that derails normal osteoblast differentiation (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional work has highlighted the presence of naturally occurring antisense transcripts that are co‐expressed with IFITM5 in osteoblasts; these non–protein coding RNAs appear to positively regulate IFITM5 expression and, by extension, osteoblast differentiation. Manipulation of these antisense transcripts can dramatically affect bone cell maturation, further emphasizing the complexity of IFITM5 regulation in bone formation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, studies employing both immunosuppressant treatments and conditional knockin models have confirmed that misexpression of mutant IFITM5 in early skeletal progenitors leads to significant disturbances in bone homeostasis including low bone mass and growth retardation. These findings not only delineate a pivotal role for IFITM5 in pre-natal bone development and endochondral ossification but also provide a mechanistic insight into how signaling alterations, such as those driven by ERK activation and SOX9 dysregulation, contribute to the clinical manifestations of osteogenesis imperfecta type V (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, while the function of MIR4666A is not directly addressed in these abstracts, the collective insights into IFITM5 (BRIL) emphasize its central role in osteoblast differentiation, matrix mineralization, and skeletal homeostasis. Should MIR4666A be part of the regulatory network controlling IFITM5 expression or function, it might be implicated in modulating these critical processes in bone formation.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroko Kimoto, Sachiko Haga, Koji Sato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature04033"}], "href": "https://doi.org/10.1038/nature04033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16208374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16208374"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Pierre Moffatt, Marie-Helene Gaumond, Patrick Salois, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bril: a novel bone-specific modulator of mineralization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1359/jbmr.080412"}], "href": "https://doi.org/10.1359/jbmr.080412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18442316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18442316"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nobutaka Hanagata, Xianglan Li, Hiromi Morita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Metab (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00774-010-0221-0"}], "href": "https://doi.org/10.1007/s00774-010-0221-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20838829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20838829"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nobutaka Hanagata, Xianglan Li "}, {"type": "b", "children": [{"type": "t", "text": "Osteoblast-enriched membrane protein IFITM5 regulates the association of CD9 with an FKBP11-CD81-FPRP complex and stimulates expression of interferon-induced genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2011.04.136"}], "href": "https://doi.org/10.1016/j.bbrc.2011.04.136"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21600883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21600883"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takashi Tsukamoto, Xianglan Li, Hiromi Morita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of S-palmitoylation on IFITM5 for the interaction with FKBP11 in osteoblast cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0075831"}], "href": "https://doi.org/10.1371/journal.pone.0075831"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24058703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24058703"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Caressa D Lietman, Ronit Marom, Elda Munivez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.2363"}], "href": "https://doi.org/10.1002/jbmr.2363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25251575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25251575"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alexa Patoine, Marie-Hélène Gaumond, Prashant K Jaiswal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Topological mapping of BRIL reveals a type II orientation and effects of osteogenesis imperfecta mutations on its cellular destination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.2243"}], "href": "https://doi.org/10.1002/jbmr.2243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24715519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24715519"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Bahar Kasaai, Marie-Hélène Gaumond, Pierre Moffatt "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.457010"}], "href": "https://doi.org/10.1074/jbc.M113.457010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23530031"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23530031"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yunshan Liu, Hui Liu, Louisa Titus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Natural antisense transcripts enhance bone formation by increasing sense IFITM5 transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bone (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bone.2012.07.024"}], "href": "https://doi.org/10.1016/j.bone.2012.07.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22884724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22884724"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Nobutaka Hanagata, Taro Takemura, Keiko Kamimura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of immunosuppressants on a mouse model of osteogenesis imperfecta type V harboring a heterozygous Ifitm5 c.-14C > T mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-78403-1"}], "href": "https://doi.org/10.1038/s41598-020-78403-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33273604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33273604"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ronit Marom, I-Wen Song, Emily C Busse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI170369"}], "href": "https://doi.org/10.1172/JCI170369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38885336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38885336"}]}]}]}