Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption
Autor: | Kang Ting, Robert Chiu, Aaron W. James, Jia Shen, Chia Soo, Mian Guo, Kazunari K. Yokoyama, Jin Hee Kwak |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
musculoskeletal diseases medicine.medical_specialty Osteoclasts Cypa SMAD Biology Bone resorption Article Bone and Bones 03 medical and health sciences Cyclophilin A Mice 0302 clinical medicine Osteoclast Internal medicine medicine Bruton's tyrosine kinase Animals Bone Resorption Endochondral ossification Mice Knockout Multidisciplinary Osteoblasts Osteoblast X-Ray Microtomography biology.organism_classification Immunohistochemistry Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Endocrinology RAW 264.7 Cells 030220 oncology & carcinogenesis Gene Knockdown Techniques biology.protein Signal Transduction |
Zdroj: | Scientific Reports |
ISSN: | 2045-2322 |
Popis: | 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. |
Databáze: | OpenAIRE |
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