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

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 MAFB (v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B). Methods: Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiological mechanisms, we utilized mice with the MCTO mutation ( Mafb MCTO/MCTO mice) to explore the role of MAFB. Results: Mafb MCTO/MCTO mice displayed focal segmental glomerulosclerosis (FSGS), mirroring the manifestations seen in MCTO patients. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Interestingly, heterozygous Mafb MCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histological abnormalities in the kidney, suggesting that excess MAFB is detrimental. We subsequently conducted RNA-seq on the glomeruli from Mafb MCTO/MCTO mice and detected pronounced up-regulation of the PI3K/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated Mafb MCTO/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 results in MAFB protein accumulation and leads to the development of FSGS in mice. These findings identify the MAFB–PI3K/AKT pathway as a key mechanism underlying MCTO-associated nephropathy.