Abstract #756 Disordered Osteoclast Development in Patients with Tophaceous Gout; Uric Acid Crystals Promote Osteoclastogenesis Through Interactions with Stromal Cells
Authors
Nicola Dalbeth, Timothy Smith, Kate Gregory, Barnaby Clark, Karen Callon, Fiona McQueen, Ian Reid, Jillian Cornish. University of Auckland, Auckland, New Zealand
Background
Any clinician who cares for patients with tophaceous gout knows how destructive this process can be. The mechanisms underlying the development of bony erosions in this condition, and what contribution the uric acid crystals themselves play in this process is unknown.
Methods
Tissue samples (blood, synovium, and tophaceous material) were collected from patients with chronic gout. Osteoclast precursor cells (CD14+/CD11b+)and post-culture osteoclast-like cells were evaluated by flow cytometry in both the peripheral blood and joint fluid. The activity of the osteoclast-like cells was confirmed by resorption of co-cultured bone slices. The effects of uric acid on osteoclast development were examined in vitro by culture with osteoclast precursor cell lines.
Results
Though patients with chronic gout did not have increased numbers of circulating osteoclast precursor cells, they did have an increased ability to form these cells in culture; this number correlated with the number of tophi seen clinically. Immunohistochemical analysis of tophi revealed numerous multinucleated cells surrounding uric acid crystals. These crystals inhibited osteoprotegerin production in bone marrow derived stromal cells, and the media of these cells cultured with uric acid promoted osteoclast formation in precursor cells.
Editorial Comment
The discoveries of additional unique biologic effector functions activated by uric acid crystals seem to increase each year. To its well-known abilities to stimulate neutrophil degranulation and respiratory burst, turn on the bradykinin system, fix complement, ligate TLR 2 and 4, and turn on the IL-1 mediated inflammasome is now added the capacity to promote osteoclastogenesis and directly impact bone erosion. This finding, if validated in other studies, provides a rationale for the use of bisphosphonate therapy in the treatment of chronic gouty arthritis.
