Enhanced osteoclastogenesis in patients with tophaceous gout: urate crystals promote osteoclast development through interactions with stromal cells.
OBJECTIVE
To analyze cellular mechanisms of bone erosion in gout.


METHODS
Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with gout were analyzed for the presence of osteoclast precursors. Fixed tophus and bone samples were analyzed by immunohistochemistry. Mechanisms of osteoclastogenesis were studied by culturing murine preosteoclast RAW 264.7 cells, bone marrow stromal ST2 cells, and human synovial fibroblasts with monosodium urate monohydrate (MSU) crystals.


RESULTS
PBMCs from patients with severe erosive gout had the preferential ability to form osteoclast-like cells in culture with RANKL and monocyte colony-stimulating factor (M-CSF). The number of PBMC-derived tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells strongly correlated with the number of tophi (r = 0.6296, P = 0.630). Patients with severe erosive and tophaceous gout also had higher circulating concentrations of RANKL and M-CSF. Furthermore, greater numbers of TRAP-positive multinucleated cells were cultured from SFMCs derived from gouty knee effusions than from paired PBMCs (P = 0.004). Immunohistochemical analysis demonstrated numerous multinucleated cells expressing osteoclast markers within tophi and at the interface between soft tissue and bone. MSU crystals did not directly promote osteoclast formation from RAW 264.7 cells in vitro. However, MSU crystals inhibited osteoprotegerin gene and protein expression in ST2 cells and human synovial fibroblasts, without significantly altering RANKL gene expression. Conditioned medium from ST2 cells cultured with MSU crystals promoted osteoclast formation from RAW 264.7 cells in the presence of RANKL.


CONCLUSIONS
Chronic tophaceous and erosive gout is characterized by enhanced osteoclast development. These data provide a rationale for the study of osteoclast-targeted therapies for the prevention of bone damage in chronic gout.
Dalbeth
Nicola
N
University of Auckland, Grafton, Auckland, New Zealand. n.dalbeth@auckland.ac.nz
Smith
Timothy
T
Nicolson
Bridget
B
Clark
Barnaby
B
Callon
Karen
K
Naot
Dorit
D
Haskard
Dorian O
DO
McQueen
Fiona M
FM
Reid
Ian R
IR
Cornish
Jillian
J
D000135:Acid Phosphatase; D000818:Animals; D001862:Bone Resorption / Q000473:pathology*; D002454:Cell Differentiation; D002460:Cell Line; D015331:Cohort Studies; D005347:Fibroblasts; D006073:Gout / Q000473:pathology*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D017154:Stromal Cells; D013582:Synovial Fluid / Q000166:cytology; D000071681:Tartrate-Resistant Acid Phosphatase; D014527:Uric Acid / Q000097:blood / Q000378:metabolism
D007527:Isoenzymes; D014527:Uric Acid; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase