Bone destruction by receptor activator of nuclear factor κB ligand-expressing T cells in chronic gouty arthritis

Abstract

IntroductionThe purpose of this study was to analyze the cellular expressions of pro-resorptive cytokines in gouty tophus tissues, to determine the capacity of monosodium urate monohydrate (MSU) crystals to induce these cytokines, and to understand the mechanisms of bone destruction in chronic gout.MethodsFourteen fixed, paraffin-embedded, uninfected tophus samples were analyzed immunohistochemically. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro with MSU crystals, and gene expression was assessed by reverse transcription-polymerase chain reaction. In vitro osteoclastogenesis was performed using PBMCs and synovial fluid mononuclear cells (SFMCs).ResultsCD4+ T cells, CD8+ T cells, CD20+ B cells and mast cells infiltrated tophus tissues. Tartrate-resistant acid phosphatase (TRAP)+ osteoclasts were present around tophi and in osteolytic lesions. Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha were produced from infiltrated mononuclear cells, whereas receptor activator of nuclear factor κB ligand (RANKL) was strongly expressed in T cells. However, osteoprotegerin (OPG) was not or was weakly expressed in tophus tissues. MSU crystals induced the expressions of IL-1, IL-6, TNF-alpha and RANKL in PBMCs, but inhibited OPG expression. In addition, the pro-resorptive cytokines were highly expressed in SFMCs of gouty arthritis patients. Furthermore, in vitro osteoclastogenesis was enhanced in SFMC cultures, but inhibited in T cell-depleted SFMC cultures.ConclusionsOur study demonstrates that RANKL-expressing T cells and TRAP+ osteoclasts are present within gouty tophus tissues, and that infiltrating cells express pro-resorptive cytokines. Furthermore, our data show that MSU crystals have the potential to induce pro-resorptive cytokines, and T cells are involved in osteoclastogenesis in chronic gout.

The Gouty Tophus: a Review

“…Patients with tophi have enhanced osteoclast formation, and numerous osteoclasts are present adjacent to eroded bone in tophaceous joints [3,55,56]. Osteoblasts may also have a role in bone loss in gout.…”

“…Factors produced within the tophus are also likely to tip the balance within bone to a proresorptive state. A recent study reported increased expression of receptor activator of nuclear factor-κB ligand (RANKL) in tophus samples from patients with gout, whereas osteoprotegerin expression was largely absent [3]. IL-1β and TNF-α expression within the tophus may also enhance bone resorption [2,3].…”

“…Pro-inflammatory factors expressed in the gouty tophus include interleukin (IL)-1β, IL-6, tumour necrosis factor-α (TNF-α) and myeloid-related proteins-8 and -14 [2][3][4]. Transforming growth factor-β (TGF-β) is also expressed in the tophus [2].…”

“…Neutrophils are rarely observed in the gouty tophus. T and B lymphocytes are found scattered throughout the coronal and fibrovascular zones at relatively low densities [2,3].…”

Pathophysiology and immunology of acute and chronic gout

“…Patients with erosive tophaceous gout have fewer osteoblasts present on bone directly adjacent to tophus than bone unaffected by tophus [49], and have osteoclasts within tophi and at the interface between soft tissue and bone [50]. In addition, recent studies demonstrated that tophus tissue was also infiltrated with www.futuremedicine.com inflammatory T cells, which express receptor activators of the NF-kB ligand, the master regulator of osteoclastogenesis, implicating their role in bone destruction [51]. Moreover, tophus-associated monocytes produce the proresorptive cytokines IL-1b, IL-6 and TNF-a, which could further promote osteoclast differentiation [51].…”