Research Article: Role of glucocorticoid-induced leucine zipper (GILZ) in inflammatory bone loss

Date Published: August 3, 2017

Publisher: Public Library of Science

Author(s): Nianlan Yang, Babak Baban, Carlos M. Isales, Xing-Ming Shi, Dominique Heymann.


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.

Partial Text

Chronic inflammatory conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease are known to cause bone loss [1, 2]. Tumor necrosis factor alpha (TNF-α), is a potent proinflammatory cytokine and plays a major pathogenic role in RA [3–5]. 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 [8–10]. Ironically, medications used to suppress inflammation such as glucocorticoids (GCs), also 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 inflammation and protecting bone [11–15]. However, these medications have many side effects including malignancies [16, 17] and cardiovascular events [17–19], among others [17, 20–25].

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting not only joints but also the skeleton leading to systemic bone loss and increased risk of fractures. TNF-α is one of the key factors responsible for inflammation and bone loss in RA [13]. Studies carried in animal models have shown that TNF-α promotes the differentiation of bone resorbing osteoclasts while inhibiting the activity of bone forming osteoblasts [13, 49, 50]. Clinical evidence show that inhibition of TNF-α is effective in suppressing inflammation but reports on the effectiveness of TNF inhibition in preventing bone loss are inconsistent [11, 12, 51, 52]. Thus, a search for new therapies is necessary.




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