| Summary: | Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia with osteolysis at the carpal and tarsal bones. Heterozygous missense mutations in the transcription factor MAFB are found in patients with MCTO. MAFB is reported to negatively regulate osteoclastogenesis in vitro. However, the in vivo function of MAFB and its relation to MCTO remains unknown. In this study, we generated zebrafish MAFB homolog <i>mafbb</i> mutant utilizing CRISPR/Cas9 technology. <i>Mafbb</i> deficient zebrafish demonstrated enhanced osteoclast cell differentiation and abnormal cartilage and bone development resembling MCTO patients. It is known that osteoclasts are hematopoietic cells derived from macrophages. Loss of <i>mafbb</i> caused selective expansion of definitive macrophages and myeloid cells, supporting that <i>mafbb</i> restricts myeloid differentiation in vivo. We also demonstrate that MAFB MCTO mutations failed to rescue the defective osteoclastogenesis in <i>mafbb<sup>−/−</sup></i> embryos, but did not affect osteoclast cells in wild type embryos. The mechanism of MCTO mutations is likely haploinsufficiency. Zebrafish <i>mafbb</i> mutant provides a useful model to study the function of MAFB in osteoclastogenesis and the related MCTO disease.
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