Role of Mel1/Prdm16 in bone differentiation and morphology

Kazuko Kaneda-Nakashima; Kaori Igawa; Mathurot Suwanruengsri; Fuke Naoyuki; Tomonaga Ichikawa; Taro Funamoto; Shuji Kurogi; Tomohisa Sekimoto; Yoshihiro Yamashita; Etsuo Chosa; Ryoji Yamaguchi; Kazuhiro Morishita

doi:10.1016/j.yexcr.2021.112969

Role of Mel1/Prdm16 in bone differentiation and morphology

Exp Cell Res. 2022 Jan 15;410(2):112969. doi: 10.1016/j.yexcr.2021.112969. Epub 2021 Dec 7.

Affiliations

¹ Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Japan; Institute of Radiation Sciences, Osaka University, Japan; MS-CORE, Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, Japan.
² Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Japan.
³ Division of Veterinary Pathology, Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Japan.
⁴ Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Japan.
⁵ Department of Orthopaedic Surgery, Faculty of Medicine, University of Miyazaki, Japan.
⁶ Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Japan; Project for Advanced Medical Research and Development, Project Research Division, Frontier Science Research Center, University of Miyazaki, Japan. Electronic address: kmorishi@med.miyazaki-u.ac.jp.

PMID: 34883111
DOI: 10.1016/j.yexcr.2021.112969

Abstract

MEL1 (MDS1/EVI1-like gene 1/PRDM16), a zinc finger protein, is located near the chromosomal breakpoint at 1p36 in human acute myeloid leukemia (AML) cells with the t (1; 3) (p36; q21) translocation. Mel1/Prdm16 is not only a causative gene of leukemia, but also has multiple regulatory functions, such as the regulation of fat metabolism. To investigate the function of Mel1/Prdm16, we generated Mel1/Prdm16-deficient mice, but homozygous deficiency (Mel1/Prdm16^-/-) was embryonic lethal at E 11.5. Heterozygous mice showed abnormal cartilage and bone formation in the postnatal skull and long bones, suggesting that Mel1/Prdm16 expression plays an important role in bone development. In osteoblast and chondrocyte cell lines, Mel1/Prdm16 promotes the differentiation of chondrocytes and regulates the differentiation of osteoblasts. Transient repression of the master regulator Runx2 is required for chondrocyte differentiation at an early stage of differentiation. However, in Mel1/Prdm16-suppressed ATDC5 cells, the initial suppression of Runx2 was lacking and its expression was upregulated at the beginning of differentiation, suggesting that chondrogenic differentiation is suppressed in Mel1/Prdm16^+/- mesenchymal progenitor cells because Runx2 expression is upregulated during the early stage of differentiation. Thus, the Mel1/Prdm16 gene may be involved in the early repression of Runx2 expression during osteochondral differentiation and promote chondrogenic differentiation.

Keywords: Bone; Cartilage; Differentiation; Mel1/Prdm16; Runx2; Transcription factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Bone Morphogenetic Protein 2 / metabolism
Bone and Bones / anatomy & histology*
Bone and Bones / cytology*
Cartilage / pathology
Cell Differentiation*
Core Binding Factor Alpha 1 Subunit / metabolism
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / metabolism*
Homeodomain Proteins / metabolism
Mice
Mice, Knockout
Models, Biological
Osteoblasts / cytology
Osteoblasts / metabolism
Osteogenesis
Signal Transduction
Transcription Factors / deficiency
Transcription Factors / metabolism*

Substances

Bone Morphogenetic Protein 2
Core Binding Factor Alpha 1 Subunit
DNA-Binding Proteins
Homeodomain Proteins
Nkx3-2 protein, mouse
Prdm16 protein, mouse
Transcription Factors