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28.06.2022 | Original Article

Transcriptional regulation of FRZB in chondrocytes by Osterix and Msx2

verfasst von: Hiroko Yagi, Yoshifumi Takahata, Tomohiko Murakami, Yuri Nakaminami, Hiromasa Hagino, Shiori Yamamoto, Shinya Murakami, Kenji Hata, Riko Nishimura

Erschienen in: Journal of Bone and Mineral Metabolism | Ausgabe 5/2022

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Abstract

Introduction

Osteoarthritis is a common joint disease that causes destruction of articular cartilage and severe inflammation surrounding knee and hip joints. However, to date, effective therapeutic reagents for osteoarthritis have not been developed because the underlying molecular mechanisms are complex. Recent genetic findings suggest that a Wnt antagonist, frizzled-related protein B (FRZB), is a potential therapeutic target for osteoarthritis. Therefore, this study aimed to examine the transcriptional regulation of FRZB in chondrocytes.

Materials and methods

Frzb/FRZB expression was assessed by RT-qPCR analyses in murine articular chondrocytes and SW1353 chondrocyte cell line. Overexpression and knockdown experiments were performed using adenovirus and lentivirus, respectively. Luciferase-reporter and chromatin immunoprecipitation assays were performed for determining transcriptional regulation. Protein–protein interaction was determined by co-immunoprecipitation analysis.

Results

Frzb was highly expressed in cartilages, especially within articular chondrocytes. Interleukin-1α markedly reduced Frzb expression in articular chondrocytes in association with cartilage destruction and increases in ADAM metallopeptidase with thrombospondin type 1 motif (Adamts) 4 and Adamts5 expression. Bone morphogenetic protein 2 (BMP2) increased FRZB expression in SW1353 cells through Smad signaling. Osterix and msh homeobox 2 (Msx2), both of which function as downstream transcription factors of BMP2, induced FRZB expression and upregulated its promoter activity. Co-immunoprecipitation results showed a physical interaction between Osterix and Msx2. Knockdown of either Osterix or Msx2 inhibited BMP2-dependent FRZB expression. Chromatin immunoprecipitation indicated a direct association of Osterix and Msx2 with the FRZB gene promoter.

Conclusion

These results suggest that BMP2 regulates FRZB expression through Osterix and Msx2.

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Titel: Transcriptional regulation of FRZB in chondrocytes by Osterix and Msx2
verfasst von: Hiroko Yagi
Yoshifumi Takahata
Tomohiko Murakami
Yuri Nakaminami
Hiromasa Hagino
Shiori Yamamoto
Shinya Murakami
Kenji Hata
Riko Nishimura
Publikationsdatum: 28.06.2022
Verlag: Springer Nature Singapore
Erschienen in: Journal of Bone and Mineral Metabolism / Ausgabe 5/2022
Print ISSN: 0914-8779
Elektronische ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-022-01345-3

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Transcriptional regulation of FRZB in chondrocytes by Osterix and Msx2