Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by inflammation of the axial skeleton and sacroiliac joints and to a lesser extent by peripheral arthritis and the involvement of some extra-articular organs comprising the gastrointestinal tract, eyes, cardiovascular system, and entheses [1]. Characteristic lesions of the skeletal system include ectopic new bone formation and syndesmophytes [2,3]. Ectopic new bone formation may impair spinal mobility, which limits daily activities and reduces quality of life [4,5]. Therefore, suppressing skeletal damage in AS is an important treatment goal.

The question as to whether inflammation and ectopic new bone formation are related or not in AS is long-standing, and hitherto remains unresolved. The first theory is that inflammation and ectopic new bone formation are related. It is postulated inflammation is initially triggered by mechanical stress or infection, leading to the bony catabolic process. Subsequently, as inflammation decreases either rapidly or slowly, the catabolic bony process is changed to an anabolic response, which results in characteristic reactive new bone formation [6,7]. Another theory is that inflammation and new bone formation are unrelated and that some unknown factors independently trigger inflammation and new bone formation [8]. However, if inflammation is associated with ectopic new bone formation, ectopic new bone formation would probably be inhibited by a strong anti-inflammatory treatment (for example, anti-tumor necrosis factor [TNF] α therapy) at an early stage. On the other hand, if inflammation and ectopic new bone formation are independently triggered by certain factors, we must find and inhibit those factors to prevent ectopic new bone formation.

Magnetic resonance imaging (MRI) studies have shown there is an increased likelihood of ectopic new bone formation on follow up MRI after 2 years in the initially inflamed vertebral corner [9,10]. Furthermore, in these MRI studies, ectopic new bone formation occurred more frequently in the inflammation subsided vertebral corners than in those showing continued inflammation [9,11]. According to another MRI study, ectopic new bone formation occurred at the same location after fatty metaplasia at the vertebral corner [12]. Importantly, it has been suggested that systemic inflammation, represented by acute phase reactant levels, could predict radiologic progression of vertebrae [13,14].

Reported results conflict as to whether ectopic bony progression can be inhibited by anti-TNFα therapy. Early large-scale clinical studies showed that anti-TNFα agents could not inhibit bony progression [15-17]. These studies compared patients treated with anti-TNFα agents during clinical trials and the patients with spinal X-rays stored in the cohort without anti-TNFα agents during same period. However, recent long-term studies have reported that anti-TNFα agents inhibit ectopic bony progression [18-20]. In the earlier large-scale clinical studies [15-17], patients were treated with an anti-TNFα agent for 2 years and compared with a historical cohort group of nearly 200 patients treated without anti-TNFα agent, whereas the recent long-term studies [18-20] included patients treated with an anti-TNFα agent in the real world for 8 to 18 years.

Wnt signaling and the role of Dickkopf (DKK) are also important topics related to ectopic bone formation in AS is. Reports regarding the roles of DKK in bone development and homeostasis diverge. Some have reported that DKK, which acts as an inhibitor of Wnt in canonical Wnt signaling, inhibits bone development. Diarra et al. [21] investigated the role of DKK in rheumatoid arthritis and AS, and found DKK1 inhibition caused the bone-destructive pattern observed in a mouse model of rheumatoid arthritis to a bone forming pattern than wild-type controls. Furthermore, DKK1^+/− mice exhibited significantly greater bone formation and bone mass [22], and DKK1 inhibited bone growth and repair during the growth stage and adolescence, but not in old age of rodents [23]. On the other hand, DKK2 is known to be a positive regulator of osteoblast maturation, and DKK2 deficiency weakens bone mineralization, increases bone resorption, and caused osteopenia [24].

A recent article by Jo et al. [25] published in the Journal of Rheumatic Diseases provide a clue to the underlying mechanism of inflammation, bony ankylosis, and DKK1. They compared the serum levels of DKK1 between 103 patients with AS and 30 healthy controls (HCs). Furthermore, they evaluated the impact of TNFα on DKK1 expression in human primary spinal enthesis cells using various molecular biology techniques and bone formation indicators. The data demonstrated that 1) AS patients showed higher serum DKK1 levels than HCs after adjusting for age, 2) TNFα treatment promoted bone formation and DKK1 expression in both control enthesis cells and those of AS, 3) enhanced bone formation by TNFα was pronounced in AS-enthesis than those of controls, 4) TNFα induced nuclear factor-κB (NF-κB) activation upregulates the DKK1 transcript level, 4) NF-κB inhibitor led to downregulate DKK1 expression in the enthesis, 5) finally, DKK1 overexpression promoted bone formation in enthesis.

It was concluded TNFα induced DKK1 expression in enthesis through NF-κB activation. Compared with previous studies, this study reported that new bone formation was achieved by TNFα associated with inflammation in AS, and that DKK1 played a role as a positive regulator, not negative regulator of bone formation. Regarding conflicting reports of DKK on bone formation in families, DKK2 acts as a positive regulator of osteoblast maturation [24]. Furthermore, Zhou et al. [26] reported that miR-483-3p induced DKK2 to increase bone formation when differentiating from pre-osteoblast to mature osteoblast. These apparently surprising results fit well with the concept proposed by Rodda and McMahon [27] that Wnt signaling acts as a negative regulator when osteoblasts have differentiated into mature osteoblasts. In the study by Jo et al. [25], the authors revealed that TNFα-induced DKK1 expression through NF-κB activation, therefore if they identify what changes occur during TNFα treatment in DKK1 knockout conditions, they could provide solid evidence about TNFα-induced DKK1 expression through NF-κB activation.

The study by Jo et al. [25] is important in many ways. First, it improves our understating of the underlying molecular mechanisms of bony ankylosis and enthesis in AS, especially the role of the TNF-NF-κB-DKK1 axis. Second, it extended the previously reported functional role of DKK1 in bone formation [28,29]. Third, it provided novel insights into the molecular linkage between TNFα and DKK1.

This article has broadened fundamental understanding of bone formation and the pathogenesis of radiographic progression in AS. In addition, this article suggests that TNFα-mediated DKK1 plays a role in the radiographic progression of AS. Further studies are needed to identify the molecular mechanisms responsible, and clinical studies to elucidate the nature of the links between Wnt signaling, inflammation and bone formation.

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