Abstract
TNF-α plays a key role in the development of rheumatoid arthritis (RA) and inflammatory bone loss. Unfortunately, treatment of RA with anti-inflammatory glucocorticoids (GCs) also causes bone loss resulting in osteoporosis. Our previous studies showed that overexpression of glucocorticoid-induced leucine zipper (GILZ), a mediator of GC’s anti-inflammatory effect, can enhance osteogenic differentiation in vitro and bone acquisition in vivo. To investigate whether GILZ could antagonize TNF-α-induced arthritic inflammation and protect bone in mice, we generated a TNF-α-GILZ double transgenic mouse line (TNF-GILZ Tg) by crossbreeding a TNF-α Tg mouse, which ubiquitously expresses human TNF-α, with a GILZ Tg mouse, which expresses mouse GILZ under the control of a 3.6kb rat type I collagen promoter fragment. Results showed that overexpression of GILZ in bone marrow mesenchymal stem/progenitor cells protected mice from TNF-α-induced inflammatory bone loss and improved bone integrity (TNF-GILZ double Tg vs. TNF-αTg, n = 12–15). However, mesenchymal cell lineage restricted GILZ expression had limited effects on TNF-α-induced arthritic inflammation as indicated by clinical scores and serum levels of inflammatory cytokines and chemokines.
Highlights
Chronic inflammatory conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease are known to cause bone loss [1, 2]
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and the skeleton leading to systemic bone loss and increased risk of fractures
We previously showed that overexpression of glucocorticoid-induced leucine zipper (GILZ) can enhance mesenchymal stem cells (MSCs) osteogenic differentiation in vitro and it promotes bone acquisition in mice [35, 37], we found that overexpression of GILZ inhibits inflammatory cytokine-induced COX-2 expression [32] and antagonizes the inhibitory effect of TNF- α on MSC osteogenic differentiation in vitro [36]
Summary
Chronic inflammatory conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease are known to cause bone loss [1, 2]. TNF-α induces inflammation by activating NF-kB and AP-1, two key inflammatory mediators that activate the transcription of an array of inflammatory genes including cyclooxygenase-2 (COX-2) [6, 7], a target of a class of anti-arthritis medications, COXIBs such as celecoxib, etoricoxib and rofecoxib. Chronic inflammation is known to result in bone loss [8,9,10]. Medications used to suppress inflammation such as glucocorticoids (GCs), cause bone loss, making an already devastating condition, e.g., rheumatoid arthritis (RA), even worse. TNF-α inhibitors such as etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab, have become a cornerstone in RA therapy because of their effectiveness in suppressing
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