Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/11/3/480 |
| _version_ | 1797540296930623488 |
|---|---|
| author | Yujie Han Weihao Shao Dan Zhong Cui Ma Xiaona Wei Abrar Ahmed Tingting Yu Wei Jing Lili Jing |
| author_facet | Yujie Han Weihao Shao Dan Zhong Cui Ma Xiaona Wei Abrar Ahmed Tingting Yu Wei Jing Lili Jing |
| author_sort | Yujie Han |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:59:01Z |
| format | Article |
| id | doaj.art-72cbe8fb160b4037bcf05d2b4758bde3 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T12:59:01Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-72cbe8fb160b4037bcf05d2b4758bde32023-11-21T11:40:25ZengMDPI AGBiomolecules2218-273X2021-03-0111348010.3390/biom11030480Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO PatientsYujie Han0Weihao Shao1Dan Zhong2Cui Ma3Xiaona Wei4Abrar Ahmed5Tingting Yu6Wei Jing7Lili Jing8Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaShanghai Children’s Medical Center, Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, ChinaDepartment of Hepatobiliary Pancreatic Surgery, Shanghai Changhai Hospital, Shanghai 200433, ChinaEngineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, ChinaMulticentric 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.https://www.mdpi.com/2218-273X/11/3/480MAFBMulticentric Carpotarsal Osteolysis (MCTO)osteoclastsmacrophage and monocyteszebrafish |
| spellingShingle | Yujie Han Weihao Shao Dan Zhong Cui Ma Xiaona Wei Abrar Ahmed Tingting Yu Wei Jing Lili Jing Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients Biomolecules MAFB Multicentric Carpotarsal Osteolysis (MCTO) osteoclasts macrophage and monocytes zebrafish |
| title | Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients |
| title_full | Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients |
| title_fullStr | Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients |
| title_full_unstemmed | Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients |
| title_short | Zebrafish <i>mafbb</i> Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients |
| title_sort | zebrafish i mafbb i mutants display osteoclast over activation and bone deformity resembling osteolysis in mcto patients |
| topic | MAFB Multicentric Carpotarsal Osteolysis (MCTO) osteoclasts macrophage and monocytes zebrafish |
| url | https://www.mdpi.com/2218-273X/11/3/480 |
| work_keys_str_mv | AT yujiehan zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT weihaoshao zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT danzhong zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT cuima zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT xiaonawei zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT abrarahmed zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT tingtingyu zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT weijing zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients AT lilijing zebrafishimafbbimutantsdisplayosteoclastoveractivationandbonedeformityresemblingosteolysisinmctopatients |