T cells as key players for bone destruction in gouty arthritis?

The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis.

bone loss by enhanced osteoclastogenesis. In the case of gout there has been evidence for an association between the occurrence of gouty tophi and bone destruction. Yet so far the mechanisms are still elusive.
In samples of gouty tissue Lee and colleagues observed osteolytic lesions close to the tophi [1]. Stromal tissue was infi ltrated with infl ammatory T cells, B cells, and mast cells, whereas the tophi themselves were surrounded by tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. Th e occurrence of the latter may be explained by the presence of the pro-resorptive cytokines IL-1β, IL-6, and TNFα in the infi ltrated stromal tissue. Th ese cytokines reportedly enhance generation and activation of osteoclasts directly or indirectly via the induction of RANKL [2]. Analyzing CD3-expressing cells, the authors further claim a key role for T cells in bone destruction, since activated T cells in the tissue upregulate the expression of RANKL, considered the master regulator of osteoclastogenesis.
Twelve years ago Kong and colleagues fi rst reported that activated T cells promote osteoclastogenesis by the expression of RANKL [3]. Meanwhile several groups investigated the relationship between T cells and osteoclasts. In many osteolytic conditions (for example, rheuma toid arthritis or periodontal disease), RANKLexpressing T cells are located at the sites of increased bone resorption [4]. Lee and colleagues added gouty arthritis to this list [1]. Interestingly, we recently reported that, in contrast to eff ector T cells, regulatory T cells suppress osteo clasto genesis [5]. In this context, the exact subpopu lation(s) of T cells and the pathways responsible for the expression of RANKL within the infl amed gouty tissue are of major interest.
Lee and colleagues and others reported that MSU crystals induce the expression and the release of the proresorptive cytokines IL-1α, IL-1β, IL-6, and TNFα in monocytes in a dose-dependent manner [6,7]. Th e upregulation and downregulation of RANKL and osteoprotegerin by MSU-stimulated T cells was observed 24 hours and, even stronger, 72 hours after co-incubation, respectively. Th e authors employed negatively selected highly enriched T cells (>95%) for their experiments, and

Abstract
The deposition of monosodium urate (MSU) crystals in synovial fl uid and tissue leads to gouty arthritis frequently associated with synovial infl ammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infi ltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis. Nevertheless, the expression of RANKL by T cells after stimulation with MSU is a new and interesting fi nding and has not yet been described. Th e authors' hypothesis of T cells promoting osteoclasts is strengthened by in vitro assays employing peripheral blood mononuclear cells or synovial fl uid mononuclear cells (SFMCs) of patients suff ering from gout. After stimulation with RANKL, SFMCs formed more osteoclasts than the peripheral blood mononuclear cells. Th is is consistent with the data of Dalbeth and colleagues [8]. Lee and colleagues further showed that T-cell depletion from SFMCs almost abrogated osteoclastogenesis. Th is fi nding is consistent with the hypothesis that T cells are a main source of RANKL under infl ammatory conditions. A recent publication, however, reported that B cells outrange T cells in the transcription of mRNA for RANKL in patients with RA [9]. In this regard, it would be interesting to perform osteoclast assays with B-celldepleted SFMCs.
In summary, bone destruction in gouty arthritis seems to be the result of an imbalance in bone remodeling. Th e overexpression of RANKL, presumably by infi ltrating T cells in a proinfl ammatory environment, promotes osteo clastogenesis. Concomitantly, the RANKL antagonist osteoprotegerin is downregulated. Tophus-associated mono cytes contribute IL-1β, IL-6, and TNFα, which act as additional promoters for osteoclast diff erentiation. Abbreviations IL, interleukin; MSU, monosodium urate; NF, nuclear factor; RANKL, receptor activator of NF-κB ligand; SFMC, synovial fl uid mononuclear cell; TNF, tumor necrosis factor.