Pathogenesis of Multicentric Carpotarsal Osteolysis

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Abstract Multicentric carpotarsal osteolysis syndrome (MCTO) is an autosomal dominant disorder that incapacitates young children and leads to life-threatening renal failure soon after. Because of its deforming, debilitating, and frequently life-threatening nature, it is understandable why it often arises spontaneously. The clinical and radiographic hallmark is carpal–tarsal bone destruction. Bones in the shoulders, elbows, and knees are also commonly affected by the destructive process. Sometimes there is generalized osteopenia. During the past 30 years, we have cared for eleven unrelated children with MCTO. In 2012, an Australian research group reported mutations within single-exon MAFB [v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (avian)] in 13 probands with MCTO. Soon after, we reported MAFB mutations for our patient cohort confirming that all MAFB mutations causing MCTO localize to a small region of the transactivation domain. MAFB is a member of the MAF family of transcription factors, and drives osteoclast activity. However, bisphosphonates, which inhibit osteoclasts, are not an effective treatment for MCTO, suggesting other bone cells are also involved. Our preliminary data showed that serum biomarkers for osteoblasts (osteocalcin, SOST, and DKK1) were significantly decreased and MMP3 (expressed in chondrocytes) and MMP7 were elevated in MCTO patients vs. age-matched controls. Therefore, we believe that both osteoblasts and chondrocytes are also affected by MAFB mutation in MCTO. We hypothesize that MCTO results from a combination of 1) defective MMP-driven degradation of the extracellular matrix during endochondral bone formation and 2) excessive osteoclast-driven osteolysis during bone remodeling. We have already developed three patient-derived induced pluripotent stem (iPS) cell lines from patients with different mutations, race, and sex. We will now develop and validate three isogenic control cell lines using CRISPR technology to correct the MAFB mutations. We will then demonstrate that MAFB mutations impact cell differentiation and function by differentiating mutant iPSCs and isogenic control cells into OBs, chondrocytes, and OCs and assessing cell differentiation and function. This will establish the patient-derived iPSC approach as a viable method to elucidate the mechanism of MCTO. This is especially important because the MCTO mouse model does not recapitulate the carpal/tarsal bone loss seen in the human disease. Understanding the mechanism of MCTO will help guide development of therapies. Further, the patient-derived iPSCs and isogenic control cells can be used to screen drug libraries or test new therapies.