Elsevier

Joint Bone Spine

Volume 80, Issue 6, December 2013, Pages 592-596
Joint Bone Spine

Review
Pathogenesis of hyperostosis: A key role for mesenchymatous cells?

https://doi.org/10.1016/j.jbspin.2013.03.013Get rights and content

Abstract

The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses.

Introduction

Although TNFα antagonists are extremely effective against the clinical manifestations of spondyloarthritides (SpAs) [1], they seem unable to slow the rate of ankylosis. This observation is galvanizing research into the mechanisms that produce syndesmophytes (vertical spicules, usually thin, developed along the outer edge of the anulus and sometimes extending to the supra- or infrajacent vertebra). Entheseal inflammation does not seem required: thus, in diffuse idiopathic skeletal hyperostosis (DISH) [2], the corner sign seen by magnetic resonance imaging (MRI) before ossifications develop is usually related to fatty infiltration, and not to inflammation. In addition, inflammatory forms of SpA without ossifications have been described [3]. Several recent studies indicate that entheseal inflammation and ossification are independent from each other and that ossification may result from repeated stress to the entheses [4]. Thus, the mechanisms underlying ossification in SpA and DISH may share similarities, a possibility that is further supported by the comparable rate of ossification in the two conditions. In a German study comparing 146 patients with SpA and 141 with DISH, the rate of progression of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was not significantly different between the two groups (3.3 ± 4.2 versus 4.1 ± 9.5, i.e. a mean of +1.3 point/year) [5]. In this study, both syndesmophytes and osteophytes (coarser ossifications that tend toward the horizontal and form at the corners of a joint or degenerated disk) were documented in both conditions. Thus, syndesmophytes were more common in the SpA group (5.7 ± 5.5 per patient) but were also seen in the DISH group (2.7 ± 2.8 per patient) and, on the other hand, osteophytes were only slightly less numerous in patients with SpA (1.0 ± 1.4 per patient) than in patients with DISH (1.4 ± 1.8 per patient) [5]. In addition, the presentations in late-onset SpA and axial psoriatic arthritis can closely resemble DISH. These data suggest that valuable lessons may be learned from recent insights into DISH pathogenesis, despite the limited functional impact of DISH compared to SpAs (ankylosis of the vertebral and costovertebral joints is not factored into the mSASSS and is absent or minimal in DISH but causes much of the spinal stiffness seen in SpAs). We will start by discussing diagnoses that must be differentiated from ankylosing SpAs and DISH, as their investigation might generate new research hypotheses.

Section snippets

Without peripheral calcifications

In Japan, up to 4% of individuals in the general population have ossification of the posterior longitudinal ligament (OPLL) predominating at the cervical spine, a prevalence nearly 80-fold that seen in Europe [6] (Table 1). DISH is also more common in Japan, suggesting a relationship between the two conditions. Furthermore, nearly one-fourth of patients with OPLL also have ossification of the anterior longitudinal ligament. Nevertheless, early hyperostosis is not confined to Asian populations:

Dog models

DISH occurs with advancing age in 1% to 3% of large non-human primates (such as baboons and gorillas) and in many other mammals (including bears, camels, horses, bison, and whales) (Table 2). DISH may be the oldest documented disease, as evidence of the disease has been found in dinosaur skeletons [13]. The most useful animal models are probably dogs. As with humans, canine hyperostosis is more common in males and with advancing age [14]. On average, hyperostosis occurs in 4% of dogs, with

Conclusion

Although the risk of severe upper airway and neurological complications associated with DISH is sufficient reason to investigate the pathogenesis of this condition [2], improved knowledge of DISH would probably lead to novel hypotheses regarding the mechanisms of the entheseal lesions seen in SpAs. Recent evidence suggests that some CD4-CD8- T-cells that strongly express the IL-23 receptor are characterized by highly selective homing to the eye, aortic arch, and entheses [58]. Research into

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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