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

key pointsMulticentric 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.

backgroundMulticentric 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 ).

methodsGiven 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.

resultsMafbMCTO/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.

conclusionsOur findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.