Abstract
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 mafbb mutant utilizing CRISPR/Cas9 technology. Mafbb 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 mafbb caused selective expansion of definitive macrophages and myeloid cells, supporting that mafbb restricts myeloid differentiation in vivo. We also demonstrate that MAFB MCTO mutations failed to rescue the defective osteoclastogenesis in mafbb−/− embryos, but did not affect osteoclast cells in wild type embryos. The mechanism of MCTO mutations is likely haploinsufficiency. Zebrafish mafbb mutant provides a useful model to study the function of MAFB in osteoclastogenesis and the related MCTO disease.
Highlights
Published: 23 March 2021The bZip factor MafB (v-maf musculoaponeurotic fibrosarcoma oncogene orthologB) is a member of the large Maf transcription factor family [1]
Mafbb is highly expressed in myeloid lineages and macrophages, we focused on mafbb
The results showed that osteoclast differentiation genes fosab and nfatc1, osteoclast maturation genes ctsk, acp5a and ocstamp [41] were all upregulated in ctsk+ cells sorted from mafbb+/− compared to wild type (WT) at 3 and 5 dpf
Summary
B) is a member of the large Maf transcription factor family [1]. It is expressed in multiple tissues including the spinal cord, retina and hematopoietic cells, and plays diverse functions in tissue development and cellular differentiation [1,2,3,4,5]. Osteoclasts are bone-resorbing cells that are derived from the hematopoietic monocytemacrophage lineage [8,9]. They are located at or near the bone surface, and degrade the bone in a specialized extracellular compartment called Howship’s lacunae by secreting acid and lytic enzymes, like tartrate-resistant acid phosphatase (TRAcP) and Cathepsin
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