Rheumatoid and pyrophosphate arthritis synovial fibroblasts induce osteoclastogenesis independently of RANKL, TNF and IL-6

Tiffany J. Dickerson, Erika Suzuki, Catherine Stanecki, Hyun Seock Shin, Hong Qui, Iannis Adamopoulos

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Bone destruction is a common feature of inflammatory arthritis and is mediated by osteoclasts, the only specialized cells to carry out bone resorption. Aberrant expression of receptor activator of nuclear factor kappa β ligand (RANKL), an inducer of osteoclast differentiation has been linked with bone pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this manuscript, we challenge the current concept that an increase in RANKL expression governs osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis. We determined a 10-fold increase of RANKL mRNA and protein in fibroblasts isolated from RA relative to PPA and OA patients. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were cultured in the presence of RA, PPA and OA synovial fibroblast conditioned medium. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), F-actin ring formation and bone resorption assays. The formation of TRAP+, VNR+ multinucleated cells, capable of F-actin ring formation and lacunar resorption in synovial fibroblast conditioned medium cultures occured in the presence of osteoprotegerin (OPG) a RANKL antagonist. Osteoclasts did not form in these cultures in the absence of macrophage colony stimulating factor (M-CSF).Our data suggest that the conditioned medium of pure synovial fibroblast cultures contain inflammatory mediators that can induce osteoclast formation in human PBMC independently of RANKL. Moreover inhibition of the TNF or IL-6 pathway was not sufficient to abolish osteoclastogenic signals derived from arthritic synovial fibroblasts. Collectively, our data clearly show that alternate osteoclastogenic pathways exist in inflammatory arthritis and place the synovial fibroblast as a key regulatory cell in bone and joint destruction, which is a hallmark of autoimmune arthritis.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalJournal of Autoimmunity
Volume39
Issue number4
DOIs
StatePublished - Dec 2012

Fingerprint

Cytoplasmic and Nuclear Receptors
Osteogenesis
Interleukin-6
Rheumatoid Arthritis
Fibroblasts
Ligands
Osteoclasts
Arthritis
Joint Diseases
Conditioned Culture Medium
Integrin alphaVbeta3
Osteoarthritis
Bone and Bones
Bone Resorption
Actins
Blood Cells
RANK Ligand
Osteoprotegerin
Macrophage Colony-Stimulating Factor
diphosphoric acid

Keywords

  • Arthritis
  • Osteoclast
  • RANKL
  • Rheumatoid arthritis
  • Synovial fibroblast

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Rheumatoid and pyrophosphate arthritis synovial fibroblasts induce osteoclastogenesis independently of RANKL, TNF and IL-6. / Dickerson, Tiffany J.; Suzuki, Erika; Stanecki, Catherine; Shin, Hyun Seock; Qui, Hong; Adamopoulos, Iannis.

In: Journal of Autoimmunity, Vol. 39, No. 4, 12.2012, p. 369-376.

Research output: Contribution to journalArticle

Dickerson, Tiffany J. ; Suzuki, Erika ; Stanecki, Catherine ; Shin, Hyun Seock ; Qui, Hong ; Adamopoulos, Iannis. / Rheumatoid and pyrophosphate arthritis synovial fibroblasts induce osteoclastogenesis independently of RANKL, TNF and IL-6. In: Journal of Autoimmunity. 2012 ; Vol. 39, No. 4. pp. 369-376.
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AU - Qui, Hong

AU - Adamopoulos, Iannis

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AB - Bone destruction is a common feature of inflammatory arthritis and is mediated by osteoclasts, the only specialized cells to carry out bone resorption. Aberrant expression of receptor activator of nuclear factor kappa β ligand (RANKL), an inducer of osteoclast differentiation has been linked with bone pathology and the synovial fibroblast in rheumatoid arthritis (RA). In this manuscript, we challenge the current concept that an increase in RANKL expression governs osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis. We determined a 10-fold increase of RANKL mRNA and protein in fibroblasts isolated from RA relative to PPA and OA patients. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were cultured in the presence of RA, PPA and OA synovial fibroblast conditioned medium. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), F-actin ring formation and bone resorption assays. The formation of TRAP+, VNR+ multinucleated cells, capable of F-actin ring formation and lacunar resorption in synovial fibroblast conditioned medium cultures occured in the presence of osteoprotegerin (OPG) a RANKL antagonist. Osteoclasts did not form in these cultures in the absence of macrophage colony stimulating factor (M-CSF).Our data suggest that the conditioned medium of pure synovial fibroblast cultures contain inflammatory mediators that can induce osteoclast formation in human PBMC independently of RANKL. Moreover inhibition of the TNF or IL-6 pathway was not sufficient to abolish osteoclastogenic signals derived from arthritic synovial fibroblasts. Collectively, our data clearly show that alternate osteoclastogenic pathways exist in inflammatory arthritis and place the synovial fibroblast as a key regulatory cell in bone and joint destruction, which is a hallmark of autoimmune arthritis.

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