Circulating mediators of bone remodeling in psoriatic arthritis: implications for disordered osteoclastogenesis and bone erosion

Psoriatic arthritis (PsA) is an inflammatory arthritis with a number of characteristic clinical features [1]. PsA is typically associated with psoriasis and psoriatic nail disease and has both peripheral articular manifestations (including synovitis, dactylitis, and enthesitis) and axial skeletal involvement. A range of bone pathologies is observed in patients with PsA [2]. Bone loss can occur, either locally in the form of bone erosion and osteolysis affecting the peripheral joints, or systemically with loss of skeletal bone mineral density (BMD) [3]. Aberrant bone formation may also occur, including peripheral juxtaarticular new bone formation, ankylosis, and syndesmophyte formation. These different bone pathologies may be observed in the same patient [4].

Bone is a metabolically active tissue that is capable of constantly remodeling in a highly coordinated manner (reviewed in [5]). Two main cell types are involved in bone remodeling: osteoclasts that resorb mineralized bone and osteoblasts that are responsible for new bone formation. Osteoclasts can be matured in vitro by culture of monocyte/macrophage precursors in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) [6, 7]. Osteoprotegerin (OPG) is a further mediator of bone remodeling, acting as a decoy receptor that prevents RANKL binding to its receptor RANK, thus inhibiting osteoclastogenesis [7]. When cultured on bone, osteoclasts derived in vitro excavate resorptive pits that are similar to the structures formed when osteoclasts degrade bone in vivo. These cells also express proteins that typify the osteoclast lineage, including tartrate-resistant acid phosphatase (TRAP). Additional soluble factors also influence bone remodeling; recent work has demonstrated that Dickkopf (Dkk-1), an inhibitor of Wnt signaling, inhibits osteoblast differentiation and function and promotes osteoclastogenesis through suppression of OPG [8‐11].

RANKL-mediated osteoclastogenesis has been implicated in the pathogenesis of bone resorption in PsA [12‐15]. In patients with PsA, osteoclasts are present at sites of bone erosion, and osteoclasts cultured in vitro from peripheral blood precursors exhibit increased resorptive activity compared with those from healthy controls [12]. Erosive disease is also associated with high numbers of circulating cells expressing CD14 and CD11b [12]. Intense RANKL expression has been demonstrated within the lining layer in the PsA joint, with more restricted sublining layer OPG expression, implicating imbalance in the RANKL/OPG axis that, in turn, may promote osteoclastogenesis [12]. However, the factors regulating the various manifestations of bone disease in PsA remain uncertain.

The aim of this study was to examine the role of soluble mediators of bone remodeling in the circulation of patients with PsA. Here, we focused on four soluble mediators that have been definitively implicated in bone remodeling in models of inflammatory arthritis; Dkk-1, M-CSF, RANKL, and OPG [11, 16‐19]. In particular, we wished to determine the relations between these mediators and patterns of bone pathology in PsA.

This study has allowed analysis of the relation between circulating factors of bone remodeling and patterns of bone pathology in PsA. The results provide further evidence for uncoupling of bone remodeling in patients with PsA. The soluble factors analyzed in this study are key regulators of bone turnover, and our data suggest that systemic expression of factors promoting osteoclastogenesis and bone loss (Dkk-1, M-CSF, RANKL) is disordered in patients with PsA.

Bone pathology in PsA may occur at a number of different sites, affecting both articular sites (erosion, osteolysis, and new bone formation) and the skeleton in a generalized manner (loss of BMD). In this study, patients with PsA were carefully characterized to identify patterns of peripheral joint bone loss and bone formation, and the relation between these patterns of bone pathology and soluble mediators of bone remodeling was analyzed. Our data indicate that the extent of bone loss at the peripheral joint is associated with elevated circulating M-CSF and RANKL concentrations, but that these factors are not associated with the extent of systemic bone loss in PsA. Furthermore, we have not identified circulating factors that are associated with peripheral new bone formation in this disease. Spinal radiographs were not obtained as part of this study, and it is possible that alterations in circulating markers of bone-remodeling factors may be associated with other forms of new bone formation in PsA, such as syndesmophyte formation in the axial skeleton. This study assessed sacroiliitis with plain radiography by using a widely recognized scoring method of established bone change. Although no relation between circulating bone-remodeling markers and sacroiliitis was observed, it is possible that that inflammation of the sacroiliac joints was underestimated by using this method, compared with a more-sensitive method such as magnetic resonance imaging [26, 27].

A key finding of this study is the elevated serum Dkk-1 concentrations with patients with PsA, compared with those in patients with psoriasis and healthy control participants. Dkk-1 has been strongly implicated in joint remodeling in inflammatory arthritis; blockade of this factor inhibits osteoclastogenesis and bone erosion in in vivo models of RA, even in the presence of persistent joint inflammation [11]. Furthermore, blockade of Dkk-1 promotes development of osteophytes in these models, indicating a role in regulation of new bone formation [11]. Elevated serum Dkk-1 concentrations have previously been reported in patients with active RA [11]. Interestingly, we have not identified a specific relation between serum Dkk-1 concentrations and patterns of bone pathology in PsA, in the form of either new bone formation or bone loss. PsA is a heterogeneous disease, and it is possible that this study was not powered to identify differences in Dkk-1 concentrations between disease subsets, which may overlap. However, these findings are consistent with a previous study of serum Dkk-1 concentrations in inflammatory arthritis, which did not show an association with radiographic damage in rheumatoid arthritis (RA) (by using the Sharp score) or ankylosing spondylitis (by using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)) [28]. The elevated serum Dkk-1 concentration in our study differs from that in the recent study of patients with inflammatory arthritis that included a small PsA group [28]. A further consideration is that serum Dkk-1 concentrations may not reflect the biologic activity of this mediator, particularly in the context of inflammatory disease [28]. Together, these observations indicate uncertainty about the role and significance of circulating concentrations of Dkk-1 in the development of bone disease in inflammatory arthritis.

M-CSF promotes macrophage survival and proliferation and is a key regulator of osteoclastogenesis [29]. This cytokine is required for culture of osteoclasts in vitro and has been strongly implicated in the pathogenesis of TNF-induced osteolysis in animal models [16, 30]. We showed that circulating concentrations of M-CSF are elevated in the patients with erosive PsA and strongly correlate with severity of peripheral erosive disease. Circulating M-CSF concentrations also correlated with the percentage of peripheral blood CD14⁺/CD11b⁺ cells in patients with PsA, but not with the number of TRAP⁺ MNCs or the number of resorptive pits after 2-week culture with M-CSF and RANKL. These results suggest that circulating M-CSF might promote survival or release of circulating osteoclast precursor cells, rather than differentiation or activity of osteoclasts. However, it should be noted that both M-CSF and RANKL were added to the osteoclast-differentiation cultures; thus, a biologic effect of M-CSF on osteoclast development or activity in vivo cannot be excluded entirely.

The factors tested in this study are likely to have specific effects within the local joint environment, which may not be entirely reflected by circulating concentrations. For example, it has been reported that OPG expression is limited to endothelial cells below the synovial membrane within the psoriatic joint [12]; in contrast, we did not identify reduced circulating OPG concentrations in patients with PsA or a relation between these concentrations and patterns of bone remodeling. Our data do raise the possibility that other circulating mediators, such as M-CSF or RANKL, may have a role as biomarkers to identify patients with PsA in whom progressive or accelerated joint damage will develop. One of the key aspects of biomarker development is feasibility, and measurement of soluble markers within the circulation, rather than within synovial tissue, is clearly a major advantage in this respect [31]. Prospective studies are required to validate these factors further as biomarkers in PsA [32].

Consistent with the work of Ritchlin et al. [12], our study also implicates RANKL in the pathogenesis of bone erosion in PsA, noting the modest correlation between circulating RANKL concentrations and measures of peripheral-joint bone loss. Furthermore, we demonstrated that the percentage of circulating CD14⁺/CD11b⁺ cells correlates with the extent of the erosive disease, and that osteoclasts arising from peripheral blood precursors have a greater capacity to resorb bone in those with more-severe erosive disease. It is of interest that circulating concentrations of both M-CSF and RANKL are associated with bone loss at a local level within the peripheral joints, but not with systemic BMD. Similar conclusions can also be made regarding the assessment of circulating osteoclast precursors. These findings imply that other factors within the local joint environment, perhaps alterations in osteoblast function or expression of proinflammatory cytokines such as TNF-α, may act in concert with these soluble mediators of bone remodeling to promote osteoclastogenesis, and, in turn, bone erosion.

This work has shown that systemic expression of soluble mediators of bone remodeling is disordered in PsA. Factors that promote osteoclastogenesis or inhibit osteoblast function are elevated in the circulation of patients with PsA and may contribute to periarticular bone loss in this disease. Prospective studies will be of interest to determine the role of these factors in progression of bone resorption and the effects of treatment in patients with PsA.