T cell‐mediated increased osteoclast formation from peripheral blood as a mechanism for crohn's disease‐associated bone loss

Abstract

The pathophysiology of osteoporosis in patients with Crohn's disease (CD) is still not completely elucidated. In this study, we evaluated osteoclastogenesis from peripheral blood cells of CD patients and studied the role of lymphocytes and inflammatory cytokines in this process. Peripheral blood mononuclear cells from seven patients with quiescent CD and matched healthy controls were isolated, and separated into T cells, B cells, and a T- and B-cell depleted fraction. In various culture combinations, osteoclast formation in the absence of the osteoclastogenic factors RANKL and M-CSF was assessed by scoring the number of tartrate-resistant acid phosphatase (TRACP) positive multinucleated cells (MNCs). Cytokine levels in culture supernatants were measured. Formation of heterogeneous cell clusters in culture was noticed; a process that was inhibited by anti-LFA-1. In CD cultures, mean cluster area was up to threefold higher than in control cultures, and shown to be induced by T cells. Over tenfold higher numbers of TRACP(+) MNCs were found in CD cultures, but exclusively in cultures containing T cells. Formation of cell clusters correlated strongly with formation of TRACP(+) MNCs. Both cell cluster formation and osteoclast formation were related to IL-17 levels in vitro. In conclusion, osteoclastogenesis, preceded by cell cluster formation, is T cell-mediated and increased in patients with quiescent CD. Our findings suggest heterotypic interactions between osteoclast precursors and T cells to be a triggering step in osteoclast formation in CD. Furthermore, our results propose a possible role for IL-17 in osteoclastogenesis in CD patients, and as such in CD-associated bone loss.

Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD

“…IL-17-deficient mice are resistant to bone destruction induced by lipopolysaccharide 12. Otherwise, Oostlander et al 3suggested a particular role for IL-17 in osteoclastogenesis in patients with CD. However, despite the implication of CD4 + T cells in inflammatory bone loss, the nature of the T cell subsets involved in this process and how they act in vivo remains unknown.…”

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35 mg once weekly or placebo, concomitant with calcium and vitamin D supplementation

“…These comprised reduction in bone mass due to trabecular thinning and reduced bone formation 13. Subsequent experiments showed that bone cells from patients with CD had a reduced growth potential and an impeded maturation, and increased potential to generate osteoclasts from peripheral blood 32 33. These mechanisms probably contribute to the pathogenesis of CD-induced bone loss and differ from osteoporosis due to ageing.…”

The Role of T Helper (TH)17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation

“…The coincidence of chronic inflammation and osteoporosis (OP) or osteoarthritis (OA) is quite anticipated and raised a debate about IL-17's contribution. Several hallmark inflammatory mediators including TNF- α , IL-1, IL-6, IFN- γ , receptor activator of NF- κ B (RANK), and RANK ligand (RANKL) are of crucial importance not only at the primary inflammation site, but also in bone metabolism [70, 71]. Although a protective role of IL-17 against bone loss has been described [72], induction of osteoclastogenesis by T H 17 cells has been suggested in various inflammatory models [73].…”

“…The authors proposed that leptin and IL-6 stimulate IL-17 production and, thereby, induce RANKL-mediated osteoclastogenesis. A direct link of IL-17 to osteoclast induction was proved in cultures of PBMCs drained from patients with Crohn's disease [71]. Altogether, IL-17 may be a valuable target for controlling bone diseases, at least those accompanying chronic inflammations as in Crohn's disease or inflammatory arthritis.…”