BOSTON, Massachusetts—Bone erosion in patients with severe gout may be partly due to disordered osteoclast development triggered by the effect of monosodium urate (MSU) crystals on stromal cells. Nicola Dalbeth, MD, and colleagues with the University of Aukland, New Zealand, suggested at the American College of Rheumatology 2007 meeting that this might result in an excess of bone-resorbing cells in the synovial fluid of gouty joints.¹ Such preosteoclast cells were found nestled around uric acid crystal deposits in tophi samples.

"Chronic tophaceous gout is characterized by disordered osteoclast development," Dr. Dalbeth said. "MSU crystals may promote osteoclastogenesis by alteration of the RANKL/OPG balance in stromal cells. This provides some rationale for the study of strategies that target the osteoclast for prevention of bone erosion in gout."

Dr. Dalbeth explained that osteoclasts develop from monocyte/macrophage precursors via a process mediated by stromal factors. "Chronic tophaceous gout is characterized by bone erosion and associated joint damage. The aim of this work was to study the mechanisms of bone erosion in gout, focusing on osteoclast development and function," she said.

More osteoclast-like percursors in joint fluid than in blood

The researchers collected blood (n = 20), synovial fluid (n = 8), and tophus (n = 9) samples from patients with chronic gout. They used flow cytometry to count the number of osteoclast-like precursors (OCPs) in peripheral blood and synovial fluid mononuclear cells. In addition, they analyzed the number of osteoclast-like cells (tartrate resistant acid phosphatase (TRAP) positive multinucleated cells) following culture in receptor activator of nuclear factor-ĸB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). The cells were cultured on bone slices to determine their bone-resorbing capacity.

Patients had plain radiographs of the hands measuring erosions using a modified Sharp-van der Heijde scoring method. The researchers used immunohistochemistry to analyze fixed tophus samples. Finally, they studied mechanisms of osteoclastogenesis in vitro by culturing murine preosteoclast RAW264.7 cells and bone marrow stromal ST2 cells with MSU crystals.

Dr. Dalbeth said that they found no relationship between the patients' erosion scores and the number of OCPs in the peripheral blood samples. However, when peripheral blood mononuclear cells (PBMCs) were cultured with RANKLE and M-CSF, those from patients with tophi were significantly more able to form osteoclast-like cells than those from patients with no tophi (P = .04), and the number of osteoclast-like cells formed correlated strongly with the patient's tophus burden (r = .6296, P = .003). The number of osteoclast-like cells did not correlate with C-reactive protein levels.

Even more osteoclast-like cells were cultured from synovial-fluid mononuclear cells from gouty knee effusions than from PBMCs from the same patient (P = .004). When fixed tophus tissue samples were examined using markers for osteoclasts, Dr. Dalbeth said that many such cells were found, but only next to sites of deposition of MSU crystals. "We found these cells at the interface between soft tissue and bone," she said. However, the researchers noted that erosion is not a direct effect of MSU crystals on bone and does not result from a direct action of MSU crystals on stromal cells. MSU crystals also did not directly promote osteoclast formation from the pre-osteoclast RAW264.7 cells in vitro.

MSU crystals inhibited osteoprotegerin gene (decoy receptor for RANKL) and protein expression in bone marrow stromal cells, without significantly altering RANKL gene expression. The researchers found that conditioned medium from bone marrow stromal cells cultured with MSU crystals did promote osteoclast formation in the presence of RANKL.


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