Targeting of the osteoclastogenic RANKL-RANK axis prevents osteoporotic bone loss and soft tissue calcification in coxsackievirus B3-infected mice

Kyunghee Lee, Hyunsoo Kim, Ho Sun Park, Keuk Jun Kim, Hoogeun Song, Hong In Shin, Han Sung Kim, Donghyun Seo, Hyun Kook, Jeong Hyeon Ko, Daewon Jeong

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Abstract

Bone mineralization is a normal physiological process, whereas ectopic calcification of soft tissues is a pathological process that leads to irreversible tissue damage. We have established a coxsackievirus B3 (CVB3)-infected mouse model that manifests both osteoporosis and ectopic calcification specifically in heart, pancreas, and lung. The CVB3-infected mice showed increased serum concentrations of both cytokines including IL-1β, TNF-α, and the receptor activator of NF-κB ligand (RANKL) that stimulate osteoclast formation and of the osteoclast-derived protein tartrate-resistant acid phosphatase 5b. They exhibited more osteoclasts in bone, with no change in the number of osteoblasts, and a decrease in bone formation and the serum concentration of osteoblastproduced osteocalcin. These results indicate that CVB3-induced osteoporosis is likely due to upregulation of osteoclast formation and function, in addition to decreased osteoblast activity. In addition, the serum in the CVB3-infected mice contained a high inorganic phosphate content, which causes ectopic calcification. RANKL treatment induced an increase in the in vitro cardiac fibroblast calcification by inorganic phosphate via the upregulation of osteogenic BMP2, SPARC, Runx2, Fra-1, and NF-κB signaling. We finally observed that i.p. administration of RANK-Fc, a recombinant antagonist of RANKL, prevented bone loss as well as ectopic calcification in CVB3-infected mice. Thus, our results indicate that RANKL may contribute to both abnormal calcium deposition in soft tissues and calcium depletion in bone. In addition, our animal model should provide a tool for the development of new therapeutic agents for calcium disturbance in soft and hard tissues.

Original languageEnglish
Pages (from-to)1623-1630
Number of pages8
JournalJournal of Immunology
Volume190
Issue number4
DOIs
Publication statusPublished - 2013 Feb 15

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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