INTRODUCTION: Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disorder with predominantly paediatric onset. Children present with multifocal osteolytic lesions accompanied by bone pain and soft tissue swelling. Patients often exhibit extraosseous co-morbidities such as psoriasis, inflammatory bowel disease, and arthritis. OBJECTIVES: Comparison of children with two different phenotypes of CRMO defined by presence or absence of extraosseous co-morbidities. METHODS: Children diagnosed with CRMO at the Motol University Hospital between 2010 and 2020 were retrospectively reviewed, and according to the absence or presence of extraosseous manifestations divided into two cohorts - bone limited CRMO and complex CRMO. The two groups were compared in terms of demographic data, age at disease onset, number and site of bone lesions, laboratory biomarker values, and need of escalation to a second-line therapy. RESULTS: Thirty-seven children (30 female, 7 male) with confirmed CRMO were included in the analysis. The mean age at disease onset was 10 years. All but 3 patients presented with multifocal disease. Twenty-three children (62%) had at least one extraosseous manifestation (13 sacroiliitis, 8 inflammatory bowel disease, 6 skin disease [acne, pustulosis, or psoriasis], 7 arthritis). Complex CRMO was associated with a significantly higher ESR rate (p = 0.0064) and CRP level (p = 0.018). The groups did not differ in number of foci or in age at disease onset. Bone lesion distribution differed between the two groups with significantly more frequent involvement of clavicle (p = 0.011) and pelvis (p = 0.038) in patients with complex CRMO. Children with complex CRMO more often needed escalation of therapy to DMARDs and biologic agents. CONCLUSION: Our data suggest that CRMO affecting solely the skeleton has milder course compared to complex CRMO with extraskeletal features. Further studies are needed to explore the clinical as well as the patient reported outcomes and promote individually tailored therapeutic strategies in both CRMO phenotypes.

• Klíčová slova
• Autoinflammatory disease, Chronic non-bacterial osteomyelitis, Chronic recurrent multifocal osteomyelitis, Inflammatory bowel disease, Sacroiliitis, Whole-body magnetic resonance imaging,
• MeSH
• artritida * MeSH
• dítě MeSH
• fenotyp MeSH
• idiopatické střevní záněty * MeSH
• lidé MeSH
• nemoci chrupavky * MeSH
• nemoci kostí * MeSH
• psoriáza * MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Chronic recurrent multifocal osteomyelitis (CRMO), also called chronic nonbacterial osteomyelitis (CNO) or nonbacterial osteomyelitis (NBO), is a rare autoinflammatory bone disease of unknown etiology. However, the number of patients properly diagnosed would increase with better knowledge of the disease. In this regard, whole-body magnetic resonance imaging (WB MRI) has been found to be a better predictor of active lesions than clinical examination. Importantly, the RINBO index (radiologic index for NBO) quantifies the involvement based on the WB MRI. Further, a chronic nonbacterial osteomyelitis MRI scoring (CROMRIS) has been developed as an online tool for assessing WB MRI. The therapy consists of non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates (pamidronate, zoledronate, etc.) and other drugs, including biologics. Pamidronate is an appropriate and safe therapy. The first pilot prospective randomised controlled trial (RCT) on pamidronate vs. placebo was carried out in adults. No RCT has been done in children yet. Besides RCTs, there are a number of issues to be explored in future, i.e. predictors of therapy effect, optimal therapy duration, predictors of therapy discontinuation and evaluation of optimal therapy protocol. Recently, the CNO clinical disease activity score (CDAS) was constructed and validated but the classification criteria are still being developed. As collaboration on this rare disease is essential, a prospective Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) was established to generate future comparative effectiveness research data.

• Klíčová slova
• SAPHO syndrome, chronic nonbacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO), diagnosis, nonbacterial osteomyelitis (NBO), pamidronate, therapy,
• Publikační typ
• časopisecké články MeSH

Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of chronic non-bacterial osteomyelitis. In children and adolescents, the metaphyses of long bones are affected most frequently, but the lesions can be found at any site on the skeleton, as well as in other organs such as the skin, eyes, gastrointestinal tract or lungs. Since the clinical signs of CRMO and its course are not invariable and clear, it is often very difficult to make a clinical diagnosis. The authors present their experience with the CRMO diagnosis in three cases. In the first patient, CRMO was localised in the left proximal tibia, left proximal femur, left sacrum and left clavicle bone. In the second patient, it was found in the left distal tibia, tarsometatarsal joints of the left foot and left distal femur. The third patient showed lesions in the inferior pubic ramus and ischial bone on the left side.With interdisciplinary co-operation it was possible to make the exact diagnosis of CRMO in all three female patients, and the disease was successfully managed. A precise therapeutic procedure could be derived from the results of randomised controlled studies which, however, cannot be made because of an infrequent occurrence of this disease. A meta-analysis of the cases so far published in the literature would be a more likely option.

• MeSH
• chronická nemoc MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• lidé MeSH
• osteomyelitida diagnóza   diagnostické zobrazování   MeSH
• recidiva MeSH
• rentgendiagnostika MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

The authors discuss the diagnostic and prognostic problem of chronic recurrent osteomyelitis (CRMO) described for the first time in 1972 by Giedione. This relatively rare disease of unknown origin is characterized by a slow onset with oedema and pain at several sites of the locomotor apparatus which occur concurrently or consecutively and are followed by relapses. The body temperature is normal or slightly elevated. CRMO is sometimes associated also with palmoplantar pustulosis. The authors evaluate six patients wih CRMO treated in 1988-1994 (4 boys and 2 girls), age 7-13 years at the onset of the disease. There were at least 2 and not more the 4 foci per patient. The clinical symptoms before the first orthopaedic examination persisted for 1-5 weeks. Concurrent skin disease was not observed. Relapses of symptoms were described in the patients at 8 sites with remissions lasting 4-16 weeks. The most frequent site in the investigated group is the distal metaphysis of the femur and proximal metaphysis of the tibia (11 times), the medial portion of the clavicle (twice) and the short bones of the toes (three times). Classical X-ray diagnosis revealed skeletal changes consistent with the appearance of acute or chronic haematogenic osteomyelitis. All-body scintigraphy 99mTc revealed an increased cumulation of the radiopharmaceutical preparation in the focus sooner than the classical X-ray picture. Bacteriological examination of specimens obtained from blood and material from the osseous foci does not identify the causal agent. FW and CRP examination gave elevated values and frequently also leucocytosis. Antibiotics administered for 4-32 weeks produced no detectable effect, non-steroid antiphlogistics mitigated subjective complaints. Sequestration was not observed in the investigated patients. Post-inflammatory premature closing of the growth zones on the short bones of the feet are found as a rule. Key words: chronic multifocal recurrent osteomyelitis, child age.

• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1β by neutrophil granulocytes. In this study, we show that in addition to IL-1β, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1β levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• buněčné linie MeSH
• cytoskeletální proteiny genetika   metabolismus   MeSH
• interleukin-1beta imunologie   metabolismus   MeSH
• kosti a kostní tkáň imunologie   patologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši transgenní MeSH
• myši MeSH
• NADPH-oxidasa 2 genetika   metabolismus   MeSH
• neutrofily imunologie   metabolismus   MeSH
• osteomyelitida genetika   imunologie   patologie   MeSH
• primární buněčná kultura MeSH
• signální transdukce genetika   imunologie   MeSH
• superoxidy imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• Cybb protein, mouse MeSH Prohlížeč
• cytoskeletální proteiny MeSH
• IL1B protein, mouse MeSH Prohlížeč
• interleukin-1beta MeSH
• NADPH-oxidasa 2 MeSH
• Pstpip2 protein, mouse MeSH Prohlížeč
• superoxidy MeSH

Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

• Klíčová slova
• IL-6/Jak/Stat3, chronic inflammation, chronic multifocal osteomyelitis, hematopoietic stem cells, niche,
• MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• hematopoéza MeSH
• interleukin-6 * genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• zánět * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-6 * MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

SAPHO is an acronym derived from capital letters of Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO). SAPHO syndrome is an umbrella term covering a constellation of bone lesions and skin manifestations. A 40-year-old male complained about his jaw and back pain, swelling of multiple joints and weight loss accompanied by physical deterioration and acne type skin lesions. Laboratory tests revealed abnormal elevation of inflammatory markers. Imaging studies illustrated multiple osteolytic bone lesions and paraosseal infiltrates. According to the set of criteria diagnosis of SAPHO syndrome was stated. The patient was treated with glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), but only high dose dexamethasone and prednisone were effective. Daily subcutaneous administration of anakinra at the dose of 100 mg was initiated due to limited response to more classical therapies. Because of planned mandibular osteosynthesis initiation of denosumab was preferred before bisphosphonates. Therapeutic response was confirmed by FDG-PET/MR after 5 months of anakinra and denosumab therapy, showing decreased accumulation of FDG in periosteal and paraosseal infiltrates. Inflammatory markers significantly decreased, bone pain deferred but skin manifestation receded only partially. Therefore the response was evaluated as partial remission.

• Klíčová slova
• Osteomyelitis, SAPHO syndrome, anakinra, denosumab, multiple bone osteolysis, osteitis,
• MeSH
• acne vulgaris * komplikace   diagnóza   MeSH
• antagonista receptoru pro interleukin 1 terapeutické užití   MeSH
• denosumab terapeutické užití   MeSH
• dospělí MeSH
• fluorodeoxyglukosa F18 terapeutické užití   MeSH
• lidé MeSH
• osteomyelitida * farmakoterapie   komplikace   mikrobiologie   MeSH
• syndrom získané hyperostózy * komplikace   farmakoterapie   diagnóza   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antagonista receptoru pro interleukin 1 MeSH
• denosumab MeSH
• fluorodeoxyglukosa F18 MeSH

INTRODUCTION: Autoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo . In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1. METHODS: To address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers. RESULTS: Our data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues. CONCLUSIONS: We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

• Klíčová slova
• PEST-family phosphatases, PSTPIP2, SHIP1, autoinflammation, chronic multifocal osteomyelitis, neutrophils,
• MeSH
• adaptorové proteiny signální transdukční * metabolismus   MeSH
• cytoskeletální proteiny * metabolismus   MeSH
• myši MeSH
• neutrofily * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční * MeSH
• cytoskeletální proteiny * MeSH
• Pstpip2 protein, mouse MeSH Prohlížeč
• reaktivní formy kyslíku MeSH

A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1β (IL-1β) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1β production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1β synthesis and disease initiation and/or progression.

• Klíčová slova
• CD45, PSTPIP2, PTPRC, autoinflammation, chronic recurrent multifocal osteomyelitis,
• MeSH
• adaptorové proteiny signální transdukční genetika   imunologie   MeSH
• antigeny CD45 genetika   imunologie   MeSH
• cytoskeletální proteiny genetika   imunologie   MeSH
• diabetes mellitus 1. typu genetika   imunologie   patologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• neutrofily imunologie   patologie   MeSH
• osteomyelitida genetika   imunologie   patologie   MeSH
• signální transdukce genetika   imunologie   MeSH
• stupeň závažnosti nemoci MeSH
• toll-like receptory genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antigeny CD45 MeSH
• cytoskeletální proteiny MeSH
• IL1B protein, mouse MeSH Prohlížeč
• interleukin-1beta MeSH
• Pstpip2 protein, mouse MeSH Prohlížeč
• Ptprc protein, mouse MeSH Prohlížeč
• toll-like receptory MeSH

Mutations in the adaptor protein PSTPIP2 are the cause of the autoinflammatory disease chronic multifocal osteomyelitis in mice. This disease closely resembles the human disorder chronic recurrent multifocal osteomyelitis, characterized by sterile inflammation of the bones and often associated with inflammation in other organs, such as the skin. The most critical process in the disease's development is the enhanced production of IL-1β. This excessive IL-1β is likely produced by neutrophils. In addition, the increased activity of macrophages, osteoclasts, and megakaryocytes has also been described. However, the molecular mechanism of how PSTPIP2 deficiency results in this phenotype is poorly understood. Part of the PSTPIP2 inhibitory function is mediated by protein tyrosine phosphatases from the proline-, glutamic acid-, serine- and threonine-rich (PEST) family, which are known to interact with the central part of this protein, but other regions of PSTPIP2 not required for PEST-family phosphatase binding were also shown to be indispensable for PSTPIP2 function. In this article, we show that PSTPIP2 binds the inhibitory enzymes Csk and SHIP1. The interaction with SHIP1 is of particular importance because it binds to the critical tyrosine residues at the C terminus of PSTPIP2, which is known to be crucial for its PEST-phosphatase-independent inhibitory effects in different cellular systems. We demonstrate that in neutrophils this region is important for the PSTPIP2-mediated suppression of IL-1β processing and that SHIP1 inhibition results in the enhancement of this processing. We also describe deregulated neutrophil response to multiple activators, including silica, Ab aggregates, and LPS, which is suggestive of a rather generalized hypersensitivity of these cells to various external stimulants.

• MeSH
• adaptorové proteiny signální transdukční genetika   imunologie   metabolismus   MeSH
• buněčné linie MeSH
• C-terminální Src kinasa MeSH
• cytoskeletální proteiny genetika   imunologie   metabolismus   MeSH
• fosfatasy antagonisté a inhibitory   imunologie   metabolismus   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• fosforylace MeSH
• inositolpolyfosfát-5-fosfatasy MeSH
• interleukin-1beta biosyntéza   MeSH
• makrofágy imunologie   MeSH
• megakaryocyty imunologie   MeSH
• molekulární sekvence - údaje MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• neutrofily imunologie   MeSH
• osteoklasty imunologie   MeSH
• osteomyelitida genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• signální transdukce imunologie   MeSH
• skupina kinas odvozených od src-genu imunologie   MeSH
• tyrosinkinasy metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zánět imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• C-terminální Src kinasa MeSH
• CSK protein, human MeSH Prohlížeč
• cytoskeletální proteiny MeSH
• fosfatasy MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• IL1B protein, mouse MeSH Prohlížeč
• inositolpolyfosfát-5-fosfatasy MeSH
• INPP5D protein, human MeSH Prohlížeč
• Inpp5d protein, mouse MeSH Prohlížeč
• interleukin-1beta MeSH
• Pstpip2 protein, mouse MeSH Prohlížeč
• skupina kinas odvozených od src-genu MeSH
• tyrosinkinasy MeSH