Osteoimmunology of Spondyloarthritis

Abstract

The mechanisms underlying the development of bone damage in the context of spondyloarthritis (SpA) are not completely understood. To date, a considerable amount of evidence indicates that several developmental pathways are crucially involved in osteoimmunology. The present review explores the biological mechanisms underlying the relationship between inflammatory dysregulation, structural progression, and osteoporosis in this diverse family of conditions. We summarize the current knowledge of bone biology and balance and the foundations of bone regulation, including bone morphogenetic protein, the Wnt pathway, and Hedgehog signaling, as well as the role of cytokines in the development of bone damage in SpA. Other areas surveyed include the pathobiology of bone damage and systemic bone loss (osteoporosis) in SpA and the effects of pharmacological treatment on focal bone damage. Lastly, we present data relative to a survey of bone metabolic assessment in SpA from Italian bone specialist rheumatology centers. The results confirm that most of the attention to bone health is given to postmenopausal subjects and that the aspect of metabolic bone health may still be underrepresented. In our opinion, it may be the time for a call to action to increase the interest in and focus on the diagnosis and management of SpA.

Keywords: osteoimmunology; pathophysiology; spondyloarthritis.

Figure 1

(A) Wnt canonical pathway: Wnt proteins bind to their co-receptor complex (Frizzled and low-density lipoprotein receptor-related protein 5/6) leading to inhibition of glycogen synthase kinase-3 (GSK3), mediated by dishevelled (Dvl) protein. Following this, β-catenin can translocate into the nucleus and, together with T cell factor (TCF)/lymphoid enhancer factor 1 (LEF), induces expression of Wnt target genes. Wnt non-canonical (Ca2+) pathway: Wnt proteins binding to the Frizzled receptor also leads to the activation of Dvl via activation of G proteins (G). Dvl leads to cytoplasmic calcium (Ca²⁺) release from the endoplasmic reticulum via phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3). Intracellular Ca²⁺, in turn, activates calcineurin, which activates the nuclear factor of activated T cells (NFAT), inducing the expression of Wnt target genes, leading to osteoblast differentiation. (B) Activation of the Wnt canonical pathway leads to osteoblast differentiation, upregulation of osteoprotegerin (OPG), and downregulation of receptor activator of nuclear factor-kappa B ligand (RANKL). Dickkopf (Dkk) and sclerostin (SOST) inhibit the Wnt canonical pathway by binding LRP5/6 and preventing the formation of the co-receptor complex and subsequent Wnt canonical signal transduction. In this setting, β-catenin is degraded by a complex composed of GSK3, casein kinase I (CKI), adenomatous polyposis coli (PCI), and Axin.

Figure 2

The cellular physiopathology of bone damage in spondyloarthritis. Different cytokines act in concert in the development of lytic and productive bone damage; in particular, dysregulated IL17 expression may act both by stimulating the osteoclast activity and by priming the multipotent bone marrow-derived stem cell (also called mesenchymal stem cell) towards the osteoblast lineage. The balance of several bone regulators (i.e., Wnt inhibitors, Noggin, BMPs, etc.) determines the final local and systemic net effects. The figure also includes the targets of several currently available drugs for the management of inflammatory arthritides.

Figure 3

(A) In patients with clinical or preclinical SpA, mechanical strain at enthesial sites may be followed by mechano-inflammation and subsequent development of enthesitis, which is induced and amplified by proinflammatory mediators. Afterwards, the dysregulated environment may evolve with the development of both pathologic bone formation (syndesmophytes, enthesiophytes), and athologic (local) bone resorption (erosions). (B) Chronic systemic inflammation is associated with impaired bone health due to the overexpression of proinflammatory cytokines and RANKL. These mediators, over time, cause a systemic increase in bone turnover, with a negative balance. The net result is osteoporosis, with reduced cortical and trabecular thickness, increased cortical porosity, and reduced trabecular connectivity.

Figure 4

Time flow of the pathologic changes in spondyloarthritis. The first phase, mainly inflammatory and pro-osteoclast, is associated with lytic changes (i.e., vertebral corners and peripheral joint erosions). Systemic inflammation is also associated with systemic bone loss (osteoporosis). Involved cytokines and IL17 dysregulation may trigger and foster local microenvironment dysregulation, especially at entheseal sites, which may eventually lead to the development of syndesmophytes/enthesophytes. While the anti-inflammatory effects of several currently available treatments are well documented, a direct effect of anti-IL17 treatment on bone pathologic proliferation, while intriguing, has still to be clinically demonstrated (dashed line).