Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification.

Pathologic soft tissue calcification can occur in both genetic and acquired clinical conditions, causing significant morbidity and mortality. Although the pathomechanisms of pathologic calcification are poorly understood, major progress has been made in recent years in defining the underlying genetic defects in Mendelian disorders of ectopic calcification. This review presents an overview of the pathophysiology of five monogenic disorders of pathologic calcification: pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, ankylosis, and progeria. These hereditary disorders, caused by mutations in genes encoding ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, CD73, progressive ankylosis protein, and lamin A/C proteins, respectively, are inorganic pyrophosphate (PPi) deficiency syndromes with reduced circulating levels of PPi, the principal physiologic inhibitor of calcium hydroxyapatite deposition in soft connective tissues. In addition to genetic diseases, PPi deficiency has been encountered in acquired clinical conditions accompanied by pathologic calcification. Because specific and effective treatments are lacking for pathologic calcification, the unifying finding of PPi deficiency suggests that PPi-targeted therapies may be beneficial to counteract pathologic soft tissue calcification in both genetic and acquired diseases.

Interleukin-17 is a critical target for the treatment of ankylosing enthesitis and psoriasis-like dermatitis in mice.

Ankylosis is a major pathological manifestation of spondyloarthropathy. The aim of this study was to evaluate the effects of anti-IL-17 therapy on spontaneous ankylosing enthesitis in mice. In this study, we used male DBA/1 mice as a spontaneous ankylosis model. Serum IL-17 concentrations were determined using enzyme-linked immunosorbent assay. Male DBA/1 mice from different litters were mixed and caged together preceding the treatment at 10 weeks (wk) of age (prophylaxis) or 21 wk of age (intervention). Treatment with anti-IL-17 antibodies or saline was initiated after caging in groups of mice and administered weekly. The onset of tarsal ankylosis was assessed by ankle swelling and histopathological examination. Pathological changes and mRNA expression levels were assessed in joints and ears obtained at the experimental end-point. We found that circulating IL-17 increased with the onset of ankylosis in male DBA/1 mice, coinciding with the onset of dermatitis. The symptoms of dermatitis corresponded to the pathological characteristics of psoriasis: acanthosis with mild hyperkeratosis, scaling, epidermal microabscess formation and augmented expression of K16, S100A8 and S100A9. Prophylactic administration of anti-IL-17 antibodies significantly prevented the development of both ankylosis and dermatitis in male DBA/1 mice caged together. On the other hand, administration of anti-IL-17 antibodies after disease onset had a lesser but significant effect on ankylosis progression but did not affect dermatitis progression. In conclusion, IL-17 is a key mediator in the pathogenic process of tarsal ankylosis and psoriasis-like dermatitis in male DBA/1 mice caged together. Thus, IL-17 is a potential therapeutic target in ankylosing enthesitis and psoriasis in humans.

Inhibition of inflammation but not ankylosis by glucocorticoids in mice: further evidence for the entheseal stress hypothesis.

INTRODUCTION: Studies in the spontaneous ankylosis model in aging male DBA/1 mice and in patients with ankylosing spondylitis provide evidence that inflammation and new tissue formation leading to joint or spine ankylosis are likely linked but largely uncoupled processes. We previously proposed the 'entheseal stress' hypothesis that defines microdamage or cell stress in the enthesis as a trigger for these disease processes. Here, we further investigated the relationship between inflammation and ankylosis by focusing on the early phase of the spontaneous arthritis model. METHODS: Aging male DBA/1 mice from different litters were caged together at the age of ten weeks and studied for signs of arthritis. A group of DBA/1 mice were treated daily with dexamethasone (0.5 µg/g body weight). Severity of disease was assessed by histomorphology and by positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) as a tracer. Bone loss in dexamethasone-treated or control mice was determined by in vivo dual-energy X-ray absorptiometry. Chemokine gene expression was studied ex vivo in dissected paws and in vitro in mesenchymal cells (periosteal and bone marrow stromal cells) by quantitative real-time PCR in the presence or absence of bone morphogenetic protein 2 (BMP2) and dexamethasone. RESULTS: Dexamethasone treatment did not affect incidence or severity of ankylosis, but led to an expected reduction in inflammation in the paws at week 15 as measured by PET tracer uptake. Treatment with dexamethasone negatively affected bone mineral density. Chemokines attracting neutrophils and lymphocytes were expressed in affected paws. In vitro, BMP2 stimulation upregulated chemokines in different mesenchymal joint-associated cell types, an effect that was inhibited by dexamethasone. CONCLUSIONS: BMP signaling may be a trigger for both inflammation and ankylosis in the spontaneous model of ankylosing enthesitis. The lack of inhibition by glucocorticoids on new bone formation while causing systemic bone loss highlights the paradoxical simultaneous loss and gain of bone in patients with ankylosing spondylitis.

Dose-dependent sustained local release of dexamethasone from biodegradable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers in the possible prevention of TMJ re-ankylosis (Arakeri's TMJ release technique).

Temporomandibular joint (TMJ) ankylosis is a devastating anatomico-pathological condition which severely affects the quality of human health. Over the last 70 years various treatments have been described to treat this distressing condition. But no single method has uniformly produced successful results. Although various surgical techniques have been improved periodically, the treatment results remain inefficient due to its recurrence as TMJ re-adhesion. Since recurrence remains as a problem in many cases, the TMJ ankylosis presents a major therapeutic challenge in head and neck surgery. The re-ankylosis is a unique phenomenon that so far has defied a full and logical explanation, based upon biological and mechanical factors that are linked together in a coherent fashion. Many factors have been implicated in the development of re-adhesion following TMJ surgery. But still the mechanism by which the TMJ re-adhesion develops is unclear. Hence, TMJ ankylosis demands an alternative effective treatment modality to prevent its recurrence as re-ankylosis. This paper postulates some critical biological factors responsible for re-ankylosis based on which a novel treatment modality is also proposed.

Blocking p38 signalling inhibits chondrogenesis in vitro but not ankylosis in a model of ankylosing spondylitis in vivo.

OBJECTIVES: To investigate p38 mitogen activated protein kinase (MAPK) signalling in an in vitro model of bone morphogenetic protein (BMP) and transforming growth factor ß (TGFß)-induced chondrogenesis and in vivo, with specific attention to its potential role in ankylosing enthesitis. METHODS: Human periosteum-derived cells (hPDCs) were cultured in pellets and stimulated with BMP2 or TGFß1 in the presence or absence of a p38 inhibitor SB203580 or proinflammatory cytokines. Chondrogenic differentiation was evaluated using quantitative PCR. Male DBA/1 mice from different litters were caged together at the age of 8 weeks and treated with SB203580 in both a preventive and therapeutic strategy. The mice were evaluated for prospective signs of arthritis and the toe joints were analysed histologically to assess disease severity. RESULTS: p38 inhibition by SB203580 and proinflammatory cytokines downregulated chondrogenic markers in pellet cultures stimulated by BMP2 or TGFß1. In contrast, the in vivo experiments resulted in an increased clinical incidence of arthritis and pathology severity score, reflecting progression towards ankylosis in mice given SB203580. CONCLUSION: Inhibition of p38 inhibited chondrogenic differentiation of progenitor cells, showing that not only the SMAD signalling pathways and also alternative activation of MAPKs including p38 contribute to chondrogenesis. Such an inhibitory effect is not found in an in vivo model of joint ankylosis and spondyloarthritis. Increased incidence and severity of disease in preventive experiments and shifts in disease stages in a therapeutic experimental set-up suggest that specific inhibition of p38 may have deleterious rather than beneficial effects.

Tuberculous sacroiliitis: a study of the diagnosis, therapy and medium-term results of 15 cases.

This report reviews the diagnosis, treatment and follow-up of 15 Chinese patients with tuberculous sacroiliitis (TBS) from 1997 to 2007. Buttock pain and lower back pain were the main complaints. All patients received antituberculosis chemotherapy treatment for at least 18 months; 10 also underwent surgery, with seven undergoing modified Smith-Petersen arthrodesis (evaluated using a visual analogue scale [VAS] for pain and the Oswestry Disability Index [ODI]). No simplex tuberculous synovitis existed at diagnosis. Bone-marrow oedema, cold abscess and soft-tissue oedema responded to antituberculosis treatment. Thirteen patients (86.7%) had satisfactory outcomes. There were also significant improvements in VAS and ODI scores post-operatively. In the chemotherapy plus surgery group, eight patients had solid bony fusions at 24 months post-operatively, while the five on chemotherapy alone presented with fibrous ankylosis at 24 months. Chemotherapy is the main treatment for TBS and modified arthrodesis is a feasible and effective method for treating severe joint destruction.

From ankylosis to pencil-in-cup deformity in psoriatic arthritis: a case report.

A 56-year-old woman with psoriatic arthritis is presented whose initially ankylosed digit was later found to develop pencil-in-cup change. The patient was treated over that period with etanercept and had no signs of active arthritis. The possible mechanisms for these changes are discussed.

¿Son las terapias biológicas las primeras modificadores de la enfermedad en la espondilitis anquilosante? / No disponible

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Actualización del Consenso de la Sociedad Española de Reumatología sobre el uso de antagonistas del TNFα en las espondiloartritis, incluida la artritis psoriásica / No disponible

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[Clinical study on chitosan for prevention of elbow adhesion].

OBJECTIVE: To study the clinical effect of chitosan on prevention of elbow adhesion after elbow arthrolysis. METHODS: Twenty six patients with elbow ankylosis were performed elbow arthrolysis, which divided into two groups, in chitosan group, 12 patients were injected 2% chitosan into the elbow joint cavity, and no chitosan used in the other 14 patients as control group. The average range of extension and flexion of elbow joint was detected to evaluate the clinical results. RESULTS: All patients were followed up 8 to 51 months, averaged 24 months. In the chitosan group, the average range of extension and flexion of elbow joint was restored to 92.9 degrees +/- 20.9 degrees, with an average increase of 55.0 degrees +/- 15.9 degrees compared with preoperation. In the control group, the average range of extension and flexion of elbow joint was restored to 75.4 degrees +/- 17.5 degrees, with an average increase of 38.2 degrees +/- 11.9 degrees. The outcome showed significant difference between the chitosan group and the control group (P < 0.01). CONCLUSION: Chitosan can prevent or reduce elbow adhesion after elbow arthrolysis.

The role of MHC class I heterodimer expression in mouse ankylosing enthesopathy.

Ankylosing enthesopathy (ANKENT) is a spontaneous mouse joint disease with strikingly similar pathology to human HLA-B27-associated enthesopathies such as ankylosing spondylitis. In C57Bl/10 mice, transgenic HLA-B*2702 as well as H2 genes have been shown to be relative risk factors for ANKENT. To investigate the role of major histocompatibility complex (MHC) class I expression in disease pathogenesis, ANKENT occurrence was compared among beta2-microglobulin (beta2m) knockout littermates with or without transgenes for HLA-B*2702 and human beta2m. In the knockout phenotype lacking beta2m, ANKENT occurrence is significantly reduced (P = 0.016). In the absence of beta2m, B*2702 is not detected on the cell membrane, nor does it increase the risk for ANKENT. This means that the previous finding that HLA-B*2702 increases susceptibility to ANKENT in C57Bl/10 mice cannot be ascribed to a transgene insertion effect. Rather, in order to increase disease susceptibility, B*2702 must be coexpressed with mouse beta2m (mo-beta2m). In contrast, when HLA-B*2702 is expressed with beta2m of human origin, disease susceptibility is not affected. Thus, both H2(b)-derived class I heterodimers and HLA-B*2702/mo-beta2m heterodimers contribute to ANKENT susceptibility.

Phosphocitrate prevents disease progression in murine progressive ankylosis.

OBJECTIVE: Mice with progressive ankylosis, a spontaneous arthropathy, were treated with phosphocitrate (PC) in vivo to determine the effect of PC on disease progression. METHODS: Two groups of mice with progressive ankylosis (matched for age, weight, and sex) were treated parenterally for 6 weeks with either PC or saline vehicle. RESULTS: Clinically, histologically, and microradiographically, there were significant differences in disease progression and severity in the PC-treated and the saline-treated mice. CONCLUSION: PC appears to inhibit disease progression in murine progressive ankylosis.

Transient inhibition of murine progressive ankylosis by indomethacin.

Murine progressive ankylosis (MPA) is an heritable disorder which produces acute arthritis and ankylosis of peripheral and axial joints similar to ankylosing spondylitis. Because indomethacin inhibits heterotopic bone formation in vivo, we studied its effects on MPA. Indomethacin was administered for 6 weeks beginning at weaning to litters from heterozygote breeder pairs. Progression curves for peripheral, spinal and thoracic joint ankylosis in treated and untreated ank/ank animals wer compared. There was no delay in ankylosis of peripheral or spinal joint ankylosis in MPA animals treated with indomethacin. interestingly, transient delay of thoracic ankylosis occurred in indomethacin treated MPA animals.

Hereditary joint disorder in progressive ankylosis (ank/ank) mice. II. Effect of high-dose hydrocortisone treatment on inflammation and intraarticular calcium hydroxyapatite deposits.

Mice homozygous for the progressive ankylosis trait develop an inflammatory joint disorder associated with the intraarticular deposition of calcium hydroxyapatite. When affected (ank/ank) mice were treated with high doses of hydrocortisone, synovitis receded, development of cartilaginous and bony osteophytes halted, and calcium hydroxyapatite accumulated in and distended the synovial spaces. No changes, however, occurred in the joint morphology of hydrocortisone-treated normal (ank/+) mice. Since inhibition of inflammation by hydrocortisone treatment did not block apatite accumulation, intraarticular deposition of hydroxyapatite occurs independent of inflammation in progressive ankylosis.