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PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2
Yuta Kishi1, Hisako Fujihara2,3, Koji Kawaguchi4
1Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. kishi-y@tsurumi-u.ac.jp.
Abstract:
Poly(ADP-ribosyl)ation is known to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, genomic stability and cell differentiation by poly(ADP-ribose) polymerase (PARP). While PARP inhibitors are presently under clinical investigation for cancer therapy, little is known about their side effects. However, PARP involvement in mesenchymal stem cell (MSC) differentiation potentiates MSC-related side effects arising from PARP inhibition. In this study, effects of PARP inhibitors on MSCs were examined. MSCs demonstrated suppressed osteogenic differentiation after 1 µM PJ34 treatment without cytotoxicity, while differentiation of MSCs into chondrocytes or adipocytes was unaffected. PJ34 suppressed mRNA induction of osteogenic markers, such as Runx2, Osterix, Bone Morphogenetic Protein-2, Osteocalcin, bone sialoprotein, and Osteopontin, and protein levels of Bone Morphogenetic Protein-2, Osterix and Osteocalcin. PJ34 treatment also inhibited transcription factor regulators such as Smad1, Smad4, Smad5 and Smad8. Extracellular mineralized matrix formation was also diminished. These results strongly suggest that PARP inhibitors are capable of suppressing osteogenic differentiation and poly(ADP-ribosyl)ation may play a physiological role in this process through regulation of BMP-2 signaling. Therefore, PARP inhibition may potentially attenuate osteogenic metabolism, implicating cautious use of PARP inhibitors for cancer treatments and monitoring of patient bone metabolism levels.
Insights
Poly(ADP-ribose) polymerase (PARP) inhibitors suppressed bone cell (osteogenic) differentiation in mesenchymal stem cells (MSCs) without causing cell death. This suggests PARP inhibitors may impact bone metabolism, requiring careful monitoring during cancer therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Stem Cell Research
Background:
- Poly(ADP-ribosyl)ation, mediated by poly(ADP-ribose) polymerase (PARP), is crucial for DNA repair, cell death, and differentiation.
- PARP inhibitors are investigated for cancer therapy, but their side effects, particularly on mesenchymal stem cells (MSCs), are not well understood.
- PARP's role in MSC differentiation suggests potential side effects related to bone metabolism.
Purpose of the Study:
- To investigate the effects of PARP inhibitors on MSC differentiation.
- To determine if PARP inhibition impacts osteogenic, chondrogenic, or adipogenic differentiation pathways.
- To elucidate the molecular mechanisms underlying PARP inhibitor-induced changes in MSC differentiation.
Main Methods:
- Treatment of MSCs with the PARP inhibitor PJ34 at a concentration of 1 µM.
- Assessment of cytotoxicity and differentiation into osteocytes, chondrocytes, and adipocytes.
- Analysis of mRNA and protein expression of key osteogenic markers and transcription factors (e.g., Runx2, Osterix, BMP-2, Smads).
- Evaluation of extracellular mineralized matrix formation.
Main Results:
- PJ34 treatment suppressed osteogenic differentiation of MSCs without inducing cytotoxicity.
- Differentiation into chondrocytes and adipocytes remained unaffected by PJ34.
- PJ34 significantly reduced the mRNA and protein levels of osteogenic markers (Runx2, Osterix, BMP-2, Osteocalcin, BSP, OPN).
- Inhibition of transcription factors Smad1, Smad4, Smad5, and Smad8 was observed.
- Extracellular mineralized matrix formation was diminished.
Conclusions:
- PARP inhibitors, specifically PJ34, can suppress osteogenic differentiation in MSCs.
- Poly(ADP-ribosyl)ation plays a physiological role in osteogenic differentiation, potentially via BMP-2 signaling.
- PARP inhibition may attenuate osteogenic metabolism, necessitating cautious use in cancer treatment and monitoring of bone metabolism.
