Using patient-derived induced pluripotent stem cells to study the role of MAFB in cartilage and bone development during MCTO disease manifestation

• Applicant: Dr. Tim Hammersen
• Subject Area: Developmental Biology ; Orthopaedics, Traumatology, Reconstructive Surgery ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545018984

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal disorder associated with mutations in the MAFB gene, yet the mechanistic link between MAFB mutations and MCTO pathogenesis remains elusive. MCTO is characterized by osteolysis of carpal and tarsal bones, leading to pain, deformities, and limited joint mobility. While excessive osteoclast activity is conventionally associated with MCTO bone loss, anti-resorptive treatments showed limited efficacy in preventing carpal and tarsal bone degradation. This suggests that MAFB mutations may affect other skeletal cells beyond osteoclasts, presumably impacting early bone development, leading to irregular chondrogenic/mesenchymal condensations and growth plate cartilage abnormalities. However, the role of MAFB in cartilage development and the cartilage-to-bone transition is currently unknown. To address this, this proposal introduces MCTO patient-derived induced pluripotent stem cells (iPSCs) as a novel model to investigate the link between MAFB mutations and MCTO pathogenesis, emphasizing cartilage and bone development, specifically chondrogenic mesenchyme condensation, growth plate cartilage development, and endochondral ossification. The research objectives involve histological and molecular evaluation of in vitro and in vivo maturation and mineralization of MAFB-mutant iPSC-derived growth plate cartilage, assessing chondrogenic condensation potential, and identifying transcriptional targets of MAFB. In addition, transcriptomic and proteomic data from MAFB-mutant and healthy iPSC-derived cartilage will be compared and cross-referenced with MAFB transcriptional target sites to identify putative targets for disease modification. In summary, this innovative approach aims to develop the first MCTO model, focusing on understanding disease progression in human, patient-derived cells. Results from this study will pave the way for more precise therapeutic approaches and assist in developing more efficient screening and monitoring strategies. In addition, this project will contribute to the broader understanding of cartilage biology by providing valuable insight into the role of MAFB during endochondral development.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: April Craft, Ph.D.