title: Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption.
abstract: CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia(-/-) mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia(-/-) osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia(-/-) osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton's tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c-fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis.
authors.affiliation: Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, CA 90095, USA.|Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, University of California, Los Angeles, CA 90095, USA.|Division of Plastic and Reconstructive Surgery, School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Chia B
authors.initials: CB
authors.lastname: Soo
authors.affiliation: Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, CA 90095, USA.|Jonsson Comprehensive Cancer Center and Division of Surgical Oncology, School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Chiu
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D021984:Cyclophilin A / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D000067996:RAW 264.7 Cells; D015398:Signal Transduction; D055114:X-Ray Microtomography
chemical_list: D021984:Cyclophilin A