The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation

by Selleckchem | Oct 08 2023

Osteoblast differentiation is regulated by various transcription factors, signaling molecules, and posttranslational modifiers. The histone acetyltransferase Mof (Kat8) is involved in distinct physiological processes. However, the exact role of Mof in osteoblast differentiation and growth remains unknown. Herein, we demonstrated that Mof expression with histone H4K16 acetylation increased during osteoblast differentiation. Inhibition of Mof by siRNA knockdown or small molecule inhibitor, MG149 which is a potent histone acetyltransferase inhibitor, reduced the expression level and transactivation potential of osteogenic key markers, Runx2 and Osterix, thus inhibiting osteoblast differentiation. Besides, Mof overexpression also enhanced the protein levels of Runx2 and Osterix. Mof could directly bind the promoter region of Runx2/Osterix to potentiate their mRNA levels, possibly through Mof-mediated H4K16ac to facilitate the activation of transcriptional programs. Importantly, Mof physically interacts with Runx2/Osterix for the stimulation of osteoblast differentiation. Yet, Mof knockdown showed indistinguishable effect on cell proliferation or apoptosis in MSCs and preosteoblast cells. Taken together, our results uncover Mof functioning as a novel regulator of osteoblast differentiation via the promotional effects on Runx2/Osterix and rationalize Mof as a potential therapeutic target, like possible application of inhibitor MG149 for the treatment of osteosarcoma or developing specific Mof activator to ameliorate osteoporosis.

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The passage you provided describes a study that investigated the role of the histone acetyltransferase Mof (Kat8) in osteoblast differentiation and growth. Here's a summary of the key findings:

1. Mof expression and histone H4K16 acetylation increased during osteoblast differentiation: The researchers observed that the expression of Mof and acetylation of histone H4 at the K16 residue (H4K16ac) were upregulated during the differentiation of osteoblasts.

2. Inhibition of Mof impaired osteoblast differentiation: Using siRNA knockdown or a small molecule inhibitor called MG149, which inhibits histone acetyltransferase activity, the researchers found that reducing Mof expression or activity decreased the expression levels and transactivation potential of key osteogenic markers, Runx2 and Osterix. Consequently, osteoblast differentiation was inhibited.

3. Mof overexpression enhanced the protein levels of Runx2 and Osterix: Conversely, when Mof was overexpressed, the protein levels of Runx2 and Osterix increased. This suggests that Mof plays a role in promoting the expression of these osteogenic markers.

4. Mof directly binds to the promoter region of Runx2/Osterix: The study found that Mof can bind to the promoter region of the Runx2 and Osterix genes. This binding may potentiate the expression of these genes, possibly through Mof-mediated H4K16ac, which facilitates the activation of transcriptional programs.

5. Mof physically interacts with Runx2/Osterix: The researchers discovered that Mof physically interacts with Runx2 and Osterix. This interaction is believed to contribute to the stimulation of osteoblast differentiation.

6. Mof knockdown had no significant effect on cell proliferation or apoptosis: The study found that reducing Mof expression did not noticeably affect cell proliferation or apoptosis in mesenchymal stem cells (MSCs) or preosteoblast cells. This suggests that the role of Mof in osteoblast differentiation is independent of these cellular processes.

Overall, the findings of this study identify Mof as a novel regulator of osteoblast differentiation. Mof promotes osteoblast differentiation by enhancing the expression of key osteogenic markers, Runx2 and Osterix, likely through direct binding to their promoter regions and facilitating transcriptional activation. These findings suggest that Mof could serve as a potential therapeutic target for conditions such as osteosarcoma and osteoporosis. The small molecule inhibitor MG149, which inhibits histone acetyltransferase activity, could be explored for the treatment of osteosarcoma, while specific Mof activators might be developed to ameliorate osteoporosis.