Chronic Multifocal Osteomyelitis Research Articles

Genetic background affects neutrophil activity and determines the severity of autoinflammatory osteomyelitis in mice.

The knowledge about the contribution of the innate immune system to health and disease is expanding. However, to obtain reliable results, it is critical to select appropriate mouse models for in vivo studies. Data on genetic and phenotypic changes associated with different mouse strains can assist in this task. Such data can also facilitate our understanding of how specific polymorphisms and genetic alterations affect gene function, phenotypes, and disease outcomes. Extensive information is available on genetic changes in all major mouse strains. However, comparatively little is known about their impact on immune response and in particular on innate immunity. Here, we analyzed a mouse model of chronic multifocal osteomyelitis (CMO), an autoinflammatory disease driven exclusively by the innate immune system, which is caused by an inactivating mutation in the Pstpip2 gene. We investigated how the genetic background of BALB/c, C57BL/6J, and C57BL/6NCrl strains alters the molecular mechanisms controlling disease progression. While all mice developed the disease, symptoms were significantly milder in BALB/c and partially also in C57BL/6J when compared to C57BL/6NCrl. Disease severity correlated with the number of infiltrating neutrophils and monocytes and with the production of chemokines attracting these cells to the site of inflammation. It also correlated with increased expression of genes associated with autoinflammation, rheumatoid arthritis, neutrophil activation, and degranulation, resulting in altered neutrophil activation in vivo. Together, our data demonstrate striking effects of genetic background on multiple parameters of neutrophil function and activity influencing the onset and course of the CMO disease.

РАЗВИТИЕ ХРОНИЧЕСКОГО МУЛЬТИОЧАГОВОГО НЕБАКТЕРИАЛЬНОГО ОСТЕОМИЕЛИТА У ПАЦИЕНТА С ИСХОДНО ДИАГНОСТИРОВАННЫМ СИСТЕМНЫМ ЮВЕНИЛЬНЫМ АРТРИТОМ: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

Systemic juvenile arthritis (sJA) is a special variant of chronic arthritis in children belonging to the spectrum of polygenic autoinflammatory diseases whose main features are persistent febrile fever, skin rashes, other systemic manifestations (serositis, lymphadenopathy, hepatosplenomegaly) as well as the presence of joint damage with the frequent development of destructive polyarthritis and osteonecrosis, high laboratory indicators of systemic inflammation either at the disease onset or delayed. The list of differentiated conditions includes many diseases such as infections, cancer, primary immunodeficiencies, monogenic autoinflammatory diseases etc. Authors represent a clinical case of a patient with sJA manifestations who was diagnosed with chronic multifocal nonbacterial osteomyelitis (CMNO), that demonstrates the great difficulties in diagnosis and the variability of the course of rheumatic diseases in childhood, which in its turn causes a delay in the timely prescription of effective therapy. Thus, patients with manifestations of a systemic inflammatory process, joint changes, especially those with an atypical course of the disease, pain in the bones and joints of a nocturnal nature, as well as an insufficient response to the therapy even long-term, are in need of conducting of a differential diagnostic search with the inclusion of CMNO, the ‘whole body’ mode magnetic-resonance tomography prescribed by a rheumatologist practitioner.

Defining the role of PSTPIP2 in neutrophil inflammatory function

Abstract Our lab and others have found that neutrophils isolated from Pstpip2cmo mice, that are deficient in proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), display a hyperinflammatory phenotype with increased IL-1b and ROS secretion following stimulation. The hyperactive neutrophil phenotype is critical to the spontaneous development of an autoinflammatory disorder called chronic multifocal osteomyelitis. However, there are gaps in our understanding of the underlying mechanism that leads to the observed phenotype in Pstpip2cmo mice which could further our understanding of neutrophil biology. We first infected WT and Pstpip2cmo mice with P. aeruginosa to elucidate the importance of PSTPIP2 in vivo. 24-hours post infection, Pstpip2cmo mice had significantly lower bacterial burden compared to WT mice. We found increased neutrophils and monocytes in the bronchial alveolar fluid (BAL) of infected Pstpip2cmo mice, and these neutrophils are lower in side-scatter measured by flow cytometry. Under homeostatic conditions, we observed higher numbers of neutrophils in the bone marrow, blood, and spleen of Pstpip2cmo mice, and more granulocyte progenitors. In addition to elevated cell numbers, we found increased IL-1β secretion NETosis compared to WT mice. Together these data suggest that PSTPIP2 plays a critical role in restraining neutrophilic inflammatory response to bacterial infection and affects granulopoiesis in naïve mice.

Involvement of knee and foot pathology presenting as an accompanying sign in a soldier of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is expressed as chronic multifocal osteomyelitis. There is no report to show a knee/foot lesions accompanying with SAPHO syndrome. We herein present a case of SAPHO syndrome with involvement of pathology of knee and foot, which was confirmed by obtaining the images of skeletal scintigraphy. We also described the clinical indicators and imaging features.

Scurvy, abnormal MRI, and gelatinous bone marrow in an adolescent with avoidant restrictive food intake disorder

BackgroundAlthough medical literature describes pediatric scurvy as “rare”, a growing number of case reports suggests otherwise. Patients often undergo costly and unnecessary workup due to unfamiliarity with the presentation of scurvy. This case report further supports the small yet growing literature documenting scurvy and its manifestations in patients with eating disorders.Case presentationA 15-year-old female presented to the emergency department with bilateral knee and ankle swelling and pain in the setting of chronic lower limb rash and BMI of 16.3. For years, she had restricted her diet to carbohydrates. Exam showed perifollicular petechial hemorrhagic rash with corkscrew hairs, knee edema, ankle edema with restricted range of motion, and antalgic gait. She was admitted for severe malnutrition from avoidant restrictive food intake disorder. Her hospital course was complicated by recurrent normocytic anemia and fever. Hematology workup revealed anemia from iron deficiency, vitamin K deficiency, and anemia of chronic disease. Rheumatology workup was negative. MRI findings showed dark T1 and bright T2 signals and were read as consistent with leukemia/lymphoma, chronic multifocal osteomyelitis, or Langerhans cell histiocytosis. However, bone marrow biopsy showed gelatinous transformation secondary to malnutrition. She was treated with vitamin C and a nutrition plan and her symptoms improved.ConclusionsAlthough this patient had common manifestations of scurvy, including perifollicular petechial hemorrhagic rash, joint effusions, anemia, and recurrent fevers, she still underwent an extensive workup. Clinicians should be aware that scurvy can present with multiple symptoms that mimic infectious, rheumatic, oncologic and hematological disease. Clinicians should have a high index of suspicion for scurvy in patients with malnutrition and eating disorders.

Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation.

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. 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. 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. 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.

Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway

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.

The Role of Interactions of Adaptor Protein PSTPIP2 in the Development of Autoinflammatory Disease

Abstract PSTPIP2 is an adaptor protein, which binds multiple regulators of neutrophil signaling to suppress inflammation. The compete loss of PSTPIP2 protein in the mouse strain Pstpip2cmo results in the development of autoinflammatory disease chronic multifocal osteomyelitis (CMO), a condition resembling human CRMO. The disease is driven by an overproduction of IL-1β and deregulated activity of NADPH oxidase. The main goal of this study is to analyze the effects of PSTPIP2 interactions on leukocyte signaling pathways, IL-1β processing, ROS production by NADPH oxidase, and auto inflammation in vivo. To achieve this, we have generated mice with mutations in major interaction sites in PSTPIP2 including W232 responsible for binding to PEST family phosphatases (PEST-PTP), and the C-terminal sequence containing major tyrosine phosphorylation sites known to bind inositide phosphatase SHIP1 (Pstpip2ΔC-t). W232A mutation resulted in enhanced ROS production by neutrophils and increased IL-1β cleavage. Moreover, some W232A mutants developed CMO symptoms. However, the kinetics was delayed and severity was milder, when compared to Pstpip2cmo strain. In contrast, Pstpip2ΔC-t mutants did not show any CMO symptoms or increased IL-1β cleavage. Interestingly, partially deregulated ROS production could still be measured in Pstpip2ΔC-t neutrophils. Collectively, our data demonstrate an important function of PEST-PTP binding to PSTPIP2 in the suppression of auto inflammation, while SHIP1 binding contributes to the regulation of neutrophil oxidative burst. The obtained data give us a novel perspective on PSTPIP2 interactome and extend our knowledge of the molecular interactions regulating physiological and pathological inflammation.

Majeed Syndrome: A Review of the Clinical, Genetic and Immunologic Features.

Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.

Chronic multifocal osteomyelitis: A case report and literature review

A case of chronic multifocal osteomyelitis was described in terms of its clinical manifestations, serological and imaging examinations, diagnostic criteria, treatment options, and follow-up evaluation after discharge. The pathogenesis, diagnosis, differential diagnosis and treatment of chronic multifocal osteomyelitis were reviewed, and the characteristics of autoinflammatory osteopathy were reviewed. The patient with onset from youth had developed severe skin lesions, progressive arthralgia and rachialgia. The clinical manifestation and the auxiliary examination of the patient accorded with the diagnosis of chronic multifocal osteomyelitis. After poor anti-inflammatory and analgesic effects, the switch to tumor necrosis factor alpha (TNF-α) inhibitor resulted in pain relief, normalization of inflammation indexes, and significant improvement in rash and imaging examination. Chronic recurrent multifocal osteomyelitis was a kind of autoinflammatory bone disease of multiple genes in disease with low incidence, unknown mechanism and unified diagnostic criteria. It was also known as chronic nonbacterial osteomyelitis, which was a rare, noninfectious inflammatory disorder that caused multifocallytic bone lesions characterized by periodic exacerbations and remissions. The exact pathophysiology or mechanism of the sterile bone inflammation was poorly understood, although chronic nonbacterial osteomyelitis was probably an osteoclast-mediated disease. In addition, an imbalance between pro- and anti-inflammatory cytokines was suspected to play a role. The available data so far pointed to the interplay among genetics, environmental, and immunologic factors as the causes of chronic nonbacterial osteomyelitis. Infectious etiology did not seem to play a crucial role in the pathogenesis of chronic nonbacterial osteomyelitis. It was often confused with metabolic bone disease, infection, tumor and other diseases. Its clinical manifestations were bone pain, fever, rash, fracture and so on. Laboratory examination showed significant increase in inflammatory markers. Radiographic examination revealed osteolytic or sclerosing changes. Magnetic resonance imaging was very useful for identifying bone lesions and tissue edema and was more accurate than bone emission computed tomography (ECT). Most of the patients begin to use non-steroidal anti-inflammatory drugs (NSAIDs) for treatment, but they are prone to relapse and new lesions appear. Other treatment options can be selected, including glucocorticoids, TNF-α inhibitors, bisphosphonates, methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs). Early diagnosis and treatment can prevent and reduce complications and improve prognosis.

Dysregulated NADPH Oxidase Promotes Bone Damage in Murine Model of Autoinflammatory Osteomyelitis.

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.

Mast cells enhance sterile inflammation in chronic nonbacterial osteomyelitis.

ABSTRACTChronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease, and patients with active or recurrent bone inflammation at multiple sites are diagnosed with chronic recurrent multifocal osteomyelitis (CRMO). The Chronic multifocal osteomyelitis (CMO) mouse model develops IL-1β-driven sterile bone lesions reminiscent of severe CRMO. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO. Here, we show that mast cells accumulate in inflamed tissues from CMO mice and that mast cell protease Mcpt1 can be detected in the peripheral blood. A transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) was crossed with CMO mice and the resulting mice (referred to as CMO/MC–) showed a significant delay in disease onset compared with age-matched CMO mice. At 5-6 months of age, CMO/MC– mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tissues. In bone marrow-derived mast cell cultures from CMO mice, cytokine production in response to the alarmin IL-33 was elevated compared with wild-type cultures. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls and from CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as in patients with oligoarticular juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients and patients with bacterial osteomyelitis. Together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO and provide rationale for further study of mast cells as therapeutic targets.

Update on the genetics of nonbacterial osteomyelitis in humans.

To summarize the current advances in our understanding or the genetic basis of nonbacterial osteomyelitis. Chronic recurrent multifocal osteomyelitis (CRMO) is a complex genetic disorder. Past discoveries identified several single gene defects (LPIN2, Pstpip2 and IL1RN) that cause IL-1-mediated sterile multifocal osteomyelitis. Recently Lorden et al.'s studies show that LIPIN2 deficiency can activate the NLRP3 inflammasome through alterations in the function of P2X7 receptor providing evidence that Majeed syndrome is an NLRP3 inflammasomopathy. New gene discoveries include the identification of FBLIM1 as a CRMO susceptibility gene. Mutations in FBLIM1 were found in a consanguineous family with CRMO. Fblim1 is one of the most significantly differentially expressed gene in bone from chronic multifocal osteomyelitis (cmo) mice, plays a role in IL-10-driven anti-inflammatory responses, and is involved in the physiology of bone remodeling. Lastly, new data on the putative CRMO susceptibility locus on chromosome 18 is presented here. Using Sanger sequencing, rather than microsatellite analysis, the DS18S60 susceptibility region could not be replicated in a larger cohort. CRMO occurs in humans, nonhuman primates, dogs and mice. There is a genetic component to disease but the genetic basis has only been identified for a small percentage of all cases.

Septic Chronic Multifocal Osteomyelitis in Children: A Challenging Presentation of Osteomylitis in a Low Income Country

Background: The aim of this study was to describe the clinical, biological and x-ray presentation of Septic Chronic Multifocal Osteomyelitis (SCMO) and discuss the therapeutic difficulties of this pathology in an African Sub-Saharan teaching hospital. Patients and Methods: A retrospective study was conducted in the Orthopedics and Trauma department of the university teaching hospital of Bobo-Dioulasso (Burkina Faso). Over a period of two years, we selected all cases of chronic osteomyelitis. We studied the epidemiological, diagnostic and therapeutic aspects of SCMO cases. Results: Eleven cases of SCMO were identified. The mean age of the patients was 11.8 years and the sex ratio was 1.75. There were 7 rural patients. The mean time to visit the hospital was 158 days. The most common reasons for consultation were pain (10 cases), swelling (9 cases), and fever (7 cases). Two were sickle cell patients. The most affected bones were the femur (10 cases), the tibia (9 cases) and the fibula (6 cases). The most frequent specific radiological lesions were sequestra (6 cases) followed by pandiaphysitis. Staphylococcus aureus was the most common aetiology. Treatment combined antibiotherapy and surgery (sequestrectomy and/or bone curettage and/or fistulectomy). Hip dislocations, pathological fractures and bone defect complicated the course of this disease. The therapeutic results was good in 3 patients and bad in 5 patients; the other 3 patients were lost to follow-up. Conclusion: Septic chronic multifocal osteomyelitis is a rare but formidable form of osteomyelitis in children. Therapeutic outcomes are often poor in hospitals with limited resources. The best strategy is prevention through early diagnosis and aggressive treatment of acute osteomyelitis.

Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. The exact molecular pathophysiology of CNO remains largely unknown. Provided familial clusters and the association with inflammatory disorders of the skin and intestine suggest a genetic predisposition. Recently, profound dysregulation of cytokine responses was demonstrated in CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1β release. In IL-10-deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1β was linked to bone inflammation. Further, alterations to the gut microbiome were suggested in contributing to IL-1β release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. Here, we summarize clinical presentation and treatment options in CNO/CRMO, current pathophysiological concepts, available mouse models, and promising future scientific directions.

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β–mediated osteomyelitis

Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production inPstpip2(cmo)mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease inPstpip2(cmo)mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 inPstpip2(cmo)mice provides similar protection as observed in caspase-1 and caspase-8-deficientPstpip2(cmo)mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease inPstpip2(cmo)mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseasedPtpn6(spin)neutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease inPstpip2(cmo)mice.

Whole-body MRI: non-oncological applications in paediatrics.

Whole-body magnetic resonance imaging (WBMRI) is a fast and accurate method for detecting and monitoring of diseases throughout the entire body without exposure to ionizing radiation. Among emerging non-oncological potential applications of WBMRI, rheumatological diseases play an important role. Rheumatological WBMRI applications include the evaluation of chronic multifocal recurrent osteomyelitis, dermatomyositis, fever of unknown origin, arthritis, and connective tissue diseases. Aim of this review is to give an overview of the use of WBMRI in rheumatological field.

PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk

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.

New discoveries in CRMO: IL-1β, the neutrophil, and the microbiome implicated in disease pathogenesis in Pstpip2-deficient mice.

Chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are autoinflammatory disorder(s) in which sterile osteomyelitis is frequently accompanied by inflammatory conditions of the joints, skin, or intestine. Patients with CRMO commonly have a personal or family history of psoriasis, inflammatory bowel disease, and inflammatory arthritis, suggesting shared disease pathogenesis. Work by our group and others has demonstrated that dysregulation of interleukin-1 (IL-1) signaling can drive sterile osteomyelitis in the two human monogenic forms of the disease. Recent work in the chronic multifocal osteomyelitis (cmo) mouse model demonstrates that the disease is IL-1-mediated, that neutrophils are critical effector cells and that both caspase-1 and caspase-8 play redundant roles in mediating the cleavage of pro-IL-1β into its biologically active form. Recent data in the cmo mouse demonstrate that dietary manipulation alters the cmo microbiome and can prevent the development of osteomyelitis. Further investigation is needed to determine the specific components of the diet that result in protection from disease and if this finding can be translated into a treatment for human CRMO.

Chronic recurrent multifocal Q fever osteomyelitis in children: a case report and review of the literature: Retracted.

Q fever is a common worldwide zoonosis that is often difficult to diagnose because of its variety and the fact that its clinical symptoms are highly unspecific. We present a rare case of chronic multifocal osteomyelitis caused by Coxiella burnetti in a 2-year-old girl, which has recurred on many occasions, although the patient is under treatment with the most widely accepted approaches from other studies. A systemic review of the little published literature on this patients shows that there is no universal consensus with regard to the most adequate treatment.