2. Academic Validation
  3. PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway

PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway

  • Int J Mol Sci. 2015 Oct 19;16(10):24820-38. doi: 10.3390/ijms161024820.
Yuta Kishi 1,  Hisako Fujihara 2 3,  Koji Kawaguchi 4,  Hiroyuki Yamada 5,  Ryoko Nakayama 6,  Nanami Yamamoto 7,  Yuko Fujihara 8,  Yoshiki Hamada 9,  Kazuhito Satomura 10,  Mitsuko Masutani 11 12
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. fujihara-h@tsurumi-u.ac.jp.
  • 3 Department of Oral Hygiene, Tsurumi Junior College 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. fujihara-h@tsurumi-u.ac.jp.
  • 4 Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. kawaguchi-k@tsurumi-u.ac.jp.
  • 5 Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. yamada-hi@tsurumi-u.ac.jp.
  • 6 Department of Pathology, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. nakayama-r@tsurumi-u.ac.jp.
  • 7 Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. yamamoto-nanami@tsurumi-u.ac.jp.
  • 8 Department of Oral and Maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. fujiharay-ora@h.u-tokyo.ac.jp.
  • 9 Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. hamada-y@tsurumi-u.ac.jp.
  • 10 Department of Oral Medicine and Stomatology, School of Dental Medicine, Tsurumi University 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. satomura-k@tsurumi-u.ac.jp.
  • 11 Department of Frontier Life Science, Graduate School of Biochemical Science, Nagasaki University 1-7-1 Sakamoto, Nagasaki 852-8588, Japan. mmasutan@ncc.go.jp.
  • 12 Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. mmasutan@ncc.go.jp.
PMID: 26492236 DOI: 10.3390/ijms161024820
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.

Keywords

PARP inhibitor; differentiation; mesenchymal stem cells; poly(ADP-ribosyl)ation.

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