Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption

Mian Guo, Aaron W. James, Jin Hee Kwak, Jia Shen, Kazunari K. Yokoyama, Kang Ting, Chia B. Soo, Robert H. Chiu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number22378
JournalScientific reports
Volume6
DOIs
StatePublished - Mar 2 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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