タナカ　リョウジロウ   Ryojiro Tanaka   田中　亮二郎    所属   川崎医科大学  医学部 臨床医学　小児科学    職種   特任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis.
掲載誌名	正式名：Journal of the American Society of Nephrology : JASN 略　 称：J Am Soc Nephrol ISSNコード：15333450/10466673
掲載区分	国外
著者・共著者	Toshiaki Usui, Shun Ishibashi, Ryojiro Tanaka, Naoki Morito, Michito Hamada, Natalia Gogoleva, Baoshuo Ning, Eugenia Kumaga, Mayuko Oki, Yuki Tsunakawa, Yuka Murakami, Shunya Sadaki, Sayaka Fuseya, Maho Kanai, Teppei Nishino, Yuri Inoue, Yoshinori Sato, Kei Gochi, Masahiro Shinohara, Akihiro Kuno, Hyojung Jeon, Eiji Warabi, Takashi Kudo, Seiya Mizuno, Masafumi Muratani, Michael A Levine, Kunihiro Yamagata, Satoru Takahashi
発行年月	2026/03
概要	KEY POINTS:Multicentric carpotarsal osteolysis, a rare disorder, causes progressive osteolysis and kidney failure because of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene mutations. A genome-edited mouse model carrying the multicentric carpotarsal osteolysis mutation was used to obtain a deeper understanding of this rare disease. Targeting MAFB/IGF-1/PI3K/AKT signaling may provide new treatments for multicentric carpotarsal osteolysis-related nephropathy.BACKGROUND:Multicentric carpotarsal osteolysis (MCTO) is a rare condition characterized by progressive osteolysis and often kidney failure. It is caused by autosomal dominant mutations in the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ).METHODS:Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiologic mechanisms, we used mice with the MCTO mutation ( MafbMCTO/MCTO mice) to explore the role of MAFB.RESULTS:MafbMCTO/MCTO mice displayed FSGS, mirroring the manifestations seen in patients with MCTO. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Heterozygous MafbMCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histologic abnormalities in the kidney, suggesting that excess MAFB was detrimental. We subsequently conducted RNA-seq on the glomeruli from MafbMCTO/MCTO mice and detected pronounced upregulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated MafbMCTO/MCTO mice with the inhibitor imatinib. This led to a significant decline in urinary albumin levels compared with the control group.CONCLUSIONS:Our findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.
DOI	10.1681/ASN.0000001060
PMID	41842942