Abstract
Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for death receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wt and DR3ko mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+ osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+ osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
Highlights
Increased prevalence of osteoporosis and decreased systemic bone mineral density at areas distal from affected joints are complicating factors for patients diagnosed with several forms of inflammatory arthritis (e.g. rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA)) as it can lead to significant increased risk of fracture [1,2,3,4]
These initial findings suggest that CCL2, CXCL8 and matrix metalloproteinases (MMPs)-9 are important downstream effector molecules by which death receptor 3 (DR3)/TL1A signalling drives pathologic systemic bone loss observed in the inflammatory arthritides
This is increasingly relevant as novel non-tumor necrosis factor super family (TNFSF) ligands for DR3 that impact on TL1A signalling, such as PGRN, have recently emerged [21]
Summary
Increased prevalence of osteoporosis and decreased systemic bone mineral density at areas distal from affected joints are complicating factors for patients diagnosed with several forms of inflammatory arthritis (e.g. rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA)) as it can lead to significant increased risk of fracture [1,2,3,4]. Addition of TL1A to human peripheral blood mononuclear cell (PBMC) cultures in the presence of macrophage colony stimulating factor (MCSF) and receptor activator of nuclear factor kappa B ligand (RANKL) enhanced OC formation [22] These data imply an important role of DR3/TL1A in modulating osteoclastogenesis and bone resorption, the underlying mechanisms are unclear. Increased expression of MMP-9 has been described in RA patient serum and is correlated with the collagen degradation marker hydroxyproline (OHPro), MMP-9 expression was reduced in DR3ko joints undergoing AIA [24] These initial findings suggest that CCL2, CXCL8 and MMP-9 are important downstream effector molecules by which DR3/TL1A signalling drives pathologic systemic bone loss observed in the inflammatory arthritides. Materials and methods were carried out as previously described [24,38,39] (see supplementary methods)
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