PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway.
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.
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.
Yuta
Y
Kishi
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.|Department of Oral Hygiene, Tsurumi Junior College 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, Kanagawa 230-8501, Japan. fujihara-h@tsurumi-u.ac.jp.
Hisako
H
Fujihara
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.
Koji
K
Kawaguchi
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.
Hiroyuki
H
Yamada
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.
Ryoko
R
Nakayama
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.
Nanami
N
Yamamoto
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.
Yuko
Y
Fujihara
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.
Yoshiki
Y
Hamada
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.
Kazuhito
K
Satomura
Department of Frontier Life Science, Graduate School of Biochemical Science, Nagasaki University 1-7-1 Sakamoto, Nagasaki 852-8588, Japan. mmasutan@ncc.go.jp.|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.
Mitsuko
M
Masutani
D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects; D053495:Osteopontin / Q000235:genetics; D010616:Phenanthrenes / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D055396:Bone Morphogenetic Protein 2; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015675:Osteocalcin; D053495:Osteopontin; D011064:Poly Adenosine Diphosphate Ribose
PARP inhibitor; differentiation; mesenchymal stem cells; poly(ADP-ribosyl)ation