Ossification Of Entheses Research Articles

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed destructive arthritis and enthesitis

BackgroundMcH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16–1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice.MethodsMale McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16–1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines.ResultsTissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16–1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16–1 treated groups.ConclusionsAdministration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.

Involvement of sphingosine kinase/sphingosine 1-phosphate metabolic pathway in spondyloarthritis

Spondyloarthritis (SpA) is a relatively common chronic inflammatory joint disorder, with a prevalence of about 0.2–0.5% worldwide. The primary target of the pathological process is the enthesis, where tendons and ligaments attach to underlying bone. These insertion sites are hotspots of bone formation (enthesophytes), which can lead to ankylosis. Unfortunately, the mechanisms causing the onset and progression of entheseal ossification remain largely unknown. Sphingosine 1-phosphate (S1P), a lipid generated after sphingosine phosphorylation by sphingosine kinases 1 and 2 (SK1/2), plays important roles in cell proliferation, differentiation and survival. S1P regulates fundamental biological processes such as cell cycle, inflammatory response or bone homeostasis. Indeed, S1P has been involved in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. On the other hand, the implication of S1P in SpA has not been explored yet. In the present work, we observed by ELISA that S1P content was significantly increased in the serum of SpA patients (6.1±4.2μM, n=21) compared to healthy donors (1.6±0.9μM, n=12). In vitro, gene expression of SK1 and SK2 as well as their activity were increased during differentiation of primary murine chondrocytes and osteoblasts into mineralizing cells. In addition, mRNA of the S1P-specific transporter Spns2 and S1P secretion were augmented. Using the pharmacological drugs SKi (SK pan-inhibitor), PF-543 (SK1 specific inhibitor) or K-145 (SK2 specific inhibitor), we showed that the inhibition of SK1 and/or SK2 decreased matrix mineralization, alkaline phosphatase activity and the mRNA expression of Runx2 and Bglap in chondrocytes and osteoblasts. To our knowledge, this is the first study indicating that S1P levels are significantly increased in serum from SpA patients. Moreover, we showed in vitro that SK activity was involved in the mineralization capacity of osteoblasts and chondrocytes. S1P metabolic pathway may represent an ingenious therapeutic target for SpA in the future.

Classification criteria for diffuse idiopathic skeletal hyperostosis: a lack of consensus.

DISH is a condition characterized by flowing ossifications of the spine with or without ossifications of entheses elsewhere in the body. Studies on the prevalence and pathogenesis of DISH use a variety of partly overlapping combinations of classification criteria, making meaningful comparisons across the literature difficult. The aim of this study was to systematically summarize the available criteria to support the development of a more uniform set of diagnostic/classification criteria. A search was performed in Pubmed, Embase, Cochrane Library and Web of Science using the term DISH and its synonyms. Articles were included when two independent observers agreed that the articles proposed a new set of classification criteria for DISH. All retrieved articles were evaluated for methodological quality, and the presented criteria were extracted. A total of 24 articles met the inclusion criteria. In all articles, spinal hyperostosis was required for the diagnosis of DISH. Peripheral, extraspinal manifestations were included as a (co-)requirement for the diagnosis DISH in five articles. Most discrepancies revolved around the threshold for the number of vertebral bodies affected and to defining different developmental phases of DISH. More than half of the retrieved articles described a dichotomous set of criteria and did not consider the progressive character of DISH. This systematic review summarizes the available different classification criteria for DISH, which highlights the lack of consensus on the diagnosis of (early) DISH. Consensus criteria, including consecutive phases of new bone formation that characterize DISH, can be developed based upon established diagnostic/classification criteria.

Enthesitis: The clue to the pathogenesis of spondyloarthritis?

The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface, known as the enthesis, can be the site of ossification in spondyloarthritis. The advent of high-performance imaging techniques such as magnetic resonance imaging has rekindled interest in the enthesis by providing new insights into the sequence that leads to entheseal ossification. These techniques have established initial inflammation and fatty metaplasia as key events that precede ossification. The pathophysiological mechanisms that trigger the initial inflammation probably involve multiple factors such as mechanical stress and the presence of resident cells responsive to interleukin-23 and capable of releasing proinflammatory cytokines. Research into the triggers of entheseal inflammation and ossification may thus provide the clue to the pathophysiology of spondyloarthritis.

Heterotopic ossification

The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface, known as the enthesis, can be the site of ossification in spondyloarthritis. The advent of high-performance imaging techniques such as magnetic resonance imaging has rekindled interest in the enthesis by providing new insights into the sequence that leads to entheseal ossification. These techniques have established initial inflammation and fatty metaplasia as key events that precede ossification. The pathophysiological mechanisms that trigger the initial inflammation probably involve multiple factors such as mechanical stress and the presence of resident cells responsive to interleukin-23 and capable of releasing proinflammatory cytokines. Research into the triggers of entheseal inflammation and ossification may thus provide the clue to the pathophysiology of spondyloarthritis.

Pseudopseudohypoparathyroidism With a Novel Mutation in the GNAS Gene Showing Thin Bones of Extremities and Ossification of Entheses

In article: Hamasaki H, Mukaino T, Kaneko H, Mitsui T, Moriyama S, Hasegawa T, Yanai H. Pseudopseudohypoparathyroidism With a Novel Mutation in the GNAS Gene Showing Thin Bones of Extremities and Ossification of Entheses. J Endocrinol Metab. 2013;3(6):150-152. The authors wish to make the following corrections. In the section of Case Report, Discussion and Figure 3, we stated a novel mutation in exon 1 (c.137 T > G, L46P) of the GNAS gene. “c.137 T > G, L46P” is incorrect, and “c.137 T > C, L46P” is correct. Although expression of substitution of cDNA was incorrect, expression of substitution of amino acid (L46P) was correct, which means that this correction does not have a great influence on our result. We have provided corrected version of Figure 3. J Endocrinol Metab. 2014;4(4):118 doi: http://dx.doi.org/10.14740/jem235w

Erratum to: Pseudopseudohypoparathyroidism With a Novel Mutation in the GNAS Gene Showing Thin Bones of Extremities and Ossification of Entheses

In article: Hamasaki H, Mukaino T, Kaneko H, Mitsui T, Moriyama S, Hasegawa T, Yanai H. Pseudopseudohypoparathyroidism With a Novel Mutation in the GNAS Gene Showing Thin Bones of Extremities and Ossification of Entheses. J Endocrinol Metab. 2013;3(6):150-152. The authors wish to make the following corrections. In the section of Case Report, Discussion and Figure 3, we stated a novel mutation in exon 1 (c.137 T > G, L46P) of the GNAS gene. “c.137 T > G, L46P” is incorrect, and “c.137 T > C, L46P” is correct. Although expression of substitution of cDNA was incorrect, expression of substitution of amino acid (L46P) was correct, which means that this correction does not have a great influence on our result. We have provided corrected version of Figure 3. J Endocrinol Metab. 2014;4(4):118 doi: http://dx.doi.org/10.14740/jem235w

AB1051 Dish prevalence in patients affected by severe cardiovascular diseases

BackgroundDISH is characterized by ossification of entheses and ligaments, especially the anterior spinal longitudinal ligament. It is almost asymptomatic, although polyarticular pain, morning stiffness, and limited spinal motion have been...

Pathogenesis of hyperostosis: A key role for mesenchymatous cells?

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.

Diffuse idiopathic skeletal hyperostosis (Forestier-Rotes-Querol disease): What's new?

Diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier-Rotes-Querol disease, is characterized by the ossification of the entheses (i.e., enthesopathy). The diagnosis of DISH requires at least two (according to Forestier) or three (according to Resnick) contiguous intervertebral bridges, without severe disk alterations (in contrast to degenerative spinal disease) or ankylosis of the sacroiliac or facet joints (in contrast to spondylarthritis). Although prevalence estimates vary with the number of bridges used to define the disease, the prevalence of DISH is consistently high and increases with age and obesity. Peripheral involvement is common but difficult to ascribe to DISH in the absence of typical spinal changes. Cervical spine ossification is the most extensively studied manifestation, as dysphagia due to esophageal compression may require surgery. As with spondylarthritis, vertebral fractures on a hyperostotic fused spine may escape recognition, placing the patient at risk for complications in the event of subsequent displacement. These fractures are particularly severe, as they often involve the cervical spine and can therefore, cause major neurological impairments. DISH is associated with an increased risk of metabolic syndrome (odds ratio, 3.88). Research into the pathophysiology of DISH has established that serum levels of the natural osteogenesis inhibitor Dickkopf-1 (DKK-1) are low in patients with DISH or spondylarthritis. Although this abnormality might contribute to the entheseal ossification, it has not been found consistently.

Pseudopseudohypoparathyroidism With a Novel Mutation in the GNAS Gene Showing Thin Bones of Extremities and Ossification of Entheses

Pseudopseudohypoparathyroidism (PPHP) is an extremely rare disorder caused by mutations in the GNAS gene. PPHP as well as pseudohypoparathyroidism (PHP) shows Albright hereditary osteodystrophy (AHO) such as mental retardation, round face, short stature, central obesity, short fingers and toes. Here we report a patient with PPHP and type 2 diabetes who had a novel mutation in the GNAS gene and showed atypical heterotopic ossification, ossification of entheses, and also thin bones of extremities, in addition to characteristic clinical features for AHO. J Endocrinol Metab. 2013;3(6):150-152 doi: http://dx.doi.org/10.4021/jem198w

The Association of Sacroiliac Joint Bridging With Other Enthesopathies in the Human Body

A descriptive study of the association between sacroiliac joint (extra-articular) bridging and other enthesopathies. To examine the relationship between sacroiliac joint bridging with other entheseal reaction sites in the skeleton, and its prognostic value in spinal diseases. Sacroiliac joint bridging is considered a hallmark of spinal diseases (e.g., ankylosing spondylitis). Nevertheless, its association with other enthesopathies has never been quantified and analyzed. A total of 289 human male skeletons with sacroiliac joint bridging and 127 without (of similar demographic structure) were evaluated for the presence of entheseal ossification, cartilaginous calcification, and other axial skeleton joint fusion (a total of 18 anatomic sites). The presence of diffuse idiopathic skeletal hyperostosis and spondyloarthropathy was also recorded. Sacroiliac joint bridging was strongly associated with entheseal reactions in other parts of the body. Of the sacroiliac joint bridging group, 24.91% had diffuse idiopathic skeletal hyperostosis, and 8.05% had spondyloarthropathy. The presence of sacroiliac joint bridging indicates an intensive general entheseal process in the skeleton.

T lymphocytes are not required for the spontaneous development of entheseal ossification leading to marginal ankylosis in the DBA/1 mouse.

Male mice of the DBA/1 inbred strain spontaneously develop polyarthritis and toe stiffness when they are > or =4 months old. The arthritis affects predominantly the proximal interphalangeal joints and the ankle of the hind limbs. The current study was aimed at determining the importance of T lymphocytes in this disease. Histologic sections of hindpaws from arthritic DBA/1 mice were examined. The role of T lymphocytes was studied by using mice lacking either alpha/beta or gamma/delta T cells due to a deletion in T cell receptor beta (TCRbeta) or TCRdelta genes. Arthritis was associated with a massive proliferation of connective tissue (fibroblasts) in synovium and adjacent tissues. Chondroid and bone tissue outgrowth at the entheses generated periarticular osteophytes (enthesophytes) which were deposited on the unchanged margins of the preexisting bone. In some cases, the enthesophytes enlarged enough to bridge and fuse the bones by marginal ankylosis. Articular cartilage was essentially unaffected. Abnormal chondroid tissue formation was common in stiffened toes, suggesting that the same pathology may underlie both joint stiffness and arthritis. Dividing chondrocytes were commonly seen in tendons, but without correlation with arthritis or toe stiffness. Mice lacking alpha/beta or gamma/delta T cells developed arthritis at the same incidence as control littermates. The naturally occurring arthritis in male DBA/1 mice is a T cell-independent enthesopathy characterized by periarticular hyperostosis and marginal ankylosis. This suggests that the ossification leading to peripheral ankylosis of the joints in human enthesopathies, such as diffuse idiopathic skeletal hyperostosis and seronegative spondylarthropathies, is a T cell-independent process.