title: The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis.
abstract: Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption. In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague-Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group. Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis.
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse 11, 8032 Zürich, Switzerland; Cartilage Engineering+Regeneration Laboratory, ETH Zurich, Zurich, Switzerland.
authors.forename: Bebeka
authors.initials: B
authors.lastname: Gjoksi
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse 11, 8032 Zürich, Switzerland.
authors.forename: Chafik
authors.initials: C
authors.lastname: Ghayor
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse 11, 8032 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Siegenthaler
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse 11, 8032 Zürich, Switzerland.
authors.forename: Nisarat
authors.initials: N
authors.lastname: Ruangsawasdi
authors.affiliation: Cartilage Engineering+Regeneration Laboratory, ETH Zurich, Zurich, Switzerland.
authors.forename: Marcy
authors.initials: M
authors.lastname: Zenobi-Wong
authors.affiliation: University Hospital, Division of Cranio-Maxillofacial and Oral Surgery and University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse 11, 8032 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland. Electronic address: franz.weber@zzm.uzh.ch.
authors.forename: Franz E
authors.initials: FE
authors.lastname: Weber
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling; D001862:Bone Resorption; D001842:Bone and Bones / Q000473:pathology; D002454:Cell Differentiation; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000737:chemistry*; D005260:Female; D005269:Femur / Q000473:pathology; D021621:Imaging, Three-Dimensional; D008856:Microscopy, Fluorescence; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010024:Osteoporosis / Q000139:chemically induced / Q000517:prevention & control*; D010052:Ovariectomy; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055114:X-Ray Microtomography
chemical_list: D004967:Estrogens; D011760:Pyrrolidinones; D000469:Alkaline Phosphatase; C038678:N-methylpyrrolidone
keywords: BET proteins; Bromodomain; Epigenetic; Estrogen deficiency; NMP; Osteoporosis