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Researchers at University of Tsukuba have elucidated the molecular pathogenesis of multicentric carpotarsal osteolysis (MCTO), a rare hereditary disorder that frequently results in renal failure. Using a mouse model, they demonstrated that MCTO is caused by mutations in a transcription factor expressed in glomerular epithelial cells. In addition, they found that pharmacological inhibition of the associated signaling pathway ameliorates renal dysfunction.

Tsukuba, Japan―Progressive osteolysis of the carpal and tarsal bones, commonly known as multicentric carpotarsal osteolysis (MCTO), is an ultra-rare autosomal dominant disorder caused by mutations in the transcription factor v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB). Although rare, several patients have been reported in Japan. Approximately 70% of individuals with MCTO develop progressive renal failure accompanied by massive proteinuria (MCTO-associated nephropathy), and nearly 40% progress to end-stage renal failure by adulthood. Focal segmental glomerulosclerosis is a distinct kidney pathology with unclear molecular mechanisms and no established effective treatment.

In this study, the researchers analyzed renal biopsy specimens from patients with MCTO and took advantage of a mouse model harboring the same MAFB mutation as that observed in human MCTO nephropathy. In mice, this mutation induced activation of the insulin-like growth factor 1 (IGF-1)-phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in glomerular epithelial cells. In turn, this activation led to excessive AKT phosphorylation and aberrant MAFB accumulation. Furthermore, treatment with imatinib, a tyrosine kinase inhibitor used clinically for chronic myeloid leukemia, suppressed PI3K/AKT signaling, reduced AKT phosphorylation, markedly decreased proteinuria, and attenuated glomerular injury in mutant mice. While these results were observed in mice, they provide a molecular basis for MCTO-associated nephropathy and suggest a potential therapeutic strategy for this currently untreatable condition.

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This work was supported by JSPS KAKENHI (Grant Numbers 21K16157、, 23K07691、, and 25K19479) , JST-Mirai Program (Grant Number JPMJPF2017), the Bayer Academic Support (Grant Number DGU01202J), and the grants from Sophie's Neighborhood.

Original Paper

Title of original paper:

Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis

Journal:

Journal of the American Society of Nephrology

DOI:

10.1681/ASN.0000001060

Correspondence

Professor TAKAHASHI Satoru
Institute of Medicine, University of Tsukuba

Professor HAMADA Michito
Center for Medical Sciences, Ibaraki Prefectural University of Health Sciences

Vice President TANAKA Ryojiro
Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital

Related Link

Institute of Medicine