[Constitutional diseases of bone: clinical flags]. / Quand penser à une maladie osseuse constitutionnelle ?

Constitutional diseases of bone form a heterogeneous group of rare diseases of varied phenotypic presentations with a vast genetic heterogeneity. Detected mostly in childhood, they may also be diagnosed in adulthood. Medical history, clinical examination as well as biological and radiological investigations may lead to the diagnosis, which should be confirmed genetically. Joint limitations, early osteoarthritis, hip dysplasia, bone deformity, enthesopathies, bone fragility or a small height can be warning signs of a constitutional disease of bone. Establishing the diagnosis is crucial to enable optimal medical management with a specialized multidisciplinary team.

Les maladies osseuses constitutionnelles constituent un groupe hétérogène de maladies rares de présentations phénotypiques variées et d'une grande hétérogénéité génétique. Le plus souvent détectées dans l'enfance, elles peuvent également être diagnostiquées à l'âge adulte. L'anamnèse, l'examen clinique et les bilans biologiques et radiologiques permettent d'orienter le diagnostic, qui devra être confirmé par une analyse génétique. Les limitations articulaires, l'arthrose précoce, les dysplasies de hanches, les déformations osseuses, les enthésopathies ou la fragilité osseuse ainsi qu'une petite taille sont des signes d'alerte pour rechercher une maladie osseuse constitutionnelle. Établir le diagnostic est crucial pour permettre une prise en charge optimale, multidisciplinaire et spécialisée.

Aptamer Technology and Its Applications in Bone Diseases.

Aptamers are single-stranded nucleic acids (DNA, short RNA, or other artificial molecules) produced by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology, which can be tightly and specifically combined with desired targets. As a comparable alternative to antibodies, aptamers have many advantages over traditional antibodies such as a strong chemical stability and rapid bulk production. In addition, aptamers can bind targets in various ways, and are not limited like the antigen-antibody combination. Studies have shown that aptamers have tremendous potential to diagnose and treat clinical diseases. However, only a few aptamer-based drugs have been used because of limitations of the aptamers and SELEX technology. To promote the development and applications of aptamers, we present a review of the methods optimizing the SELEX technology and modifying aptamers to boost the selection success rate and improve aptamer characteristics. In addition, we review the application of aptamers to treat bone diseases.

Micro-RNA: A Future Approach to Personalized Diagnosis of Bone Diseases.

Osteoporosis is a highly prevalent bone disease worldwide and the most studied bone-associated pathological condition. Although its diagnosis makes use of advanced and clinically relevant imaging and biochemical tools, the information suffers from several limitations and has little or no prognostic value. In this context, circulating micro-RNAs represent a potentially attractive alternative or a useful addition to the diagnostic arsenal and offer a greater prognostic potential than the conventional approaches. These short non-coding RNA molecules act as inhibitors of gene expression by targeting messenger RNAs with different degrees of complementarity, establishing a complex multilevel network, the basis for the fine modulation of gene expression that finally regulates every single activity of a cell. Micro-RNAs may passively and/or actively be released in the circulation by source cells, and being measurable in biological fluids, their concentrations may be associated to specific pathophysiological conditions. Mounting, despite debatable, evidence supports the use of micro-RNAs as markers of bone cell metabolic activity and bone diseases. Indeed, several micro-RNAs have been associated with bone mineral density, fractures and osteoporosis. However, concerns such as absence of comparability between studies and, the lack of standardization and harmonization of the methods, limit their application. In this review, we describe the pathophysiological bases of the association between micro-RNAs and the deregulation of bone cells activity and the processes that led to the identification of potential micro-RNA-based markers associated with metabolic bone diseases.

Serum Levels of CXCR4, SDF-1, MCP-1, NF-κB and ERK1/2 in Patients with Skeletal Fluorosis.

C-X-C motif chemokine receptor 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) affect bone cells and play an important role in bone and joint diseases, but the data on CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB in the serum of skeletal fluorosis (SF) patients are inconclusive. Thus, according to the "Diagnostic Criteria for Endemic Skeletal Fluorosis" (WS 192-2008), we enrolled patients with SF (n = 60) as the SF group and those without SF as the controls (n = 60). Serum levels of CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB were detected by enzyme-linked immunosorbent assays (ELISAs). Serum SDF-1, CXCR4, MCP-1 and NF-κB levels were significantly higher in the SF group than in the control group. Within the serum of SF patients, CXCR4 and SDF-1 levels were positively correlated with NF-κB levels. There was no correlation between MCP-1 levels and those of ERK1/2 or NF-κB. SDF-1 and CXCR4 may activate the NF-κB pathway, and MCP-1 affects the occurrence and development of SF by regulating osteocytes through other pathways. The SDF-1/CXCR4 axis and MCP-1 signalling pathway provide a new theoretical basis for the occurrence and development of SF.

Bone lesions of Langerhans cell histiocytosis triggered by trauma in children.

BACKGROUND: Bone lesions of Langerhans cell histiocytosis (LCH) may be triggered by trauma. METHODS: The characteristics of pediatric patients in the JLSG-02 study cohort who developed a bone lesion at the trauma site at diagnosis of LCH were analyzed retrospectively. RESULTS: Of the 261 pediatric patients with LCH, 12 (4.6%), of median age 4.9 years, had trauma-triggered bone LCH lesions at diagnosis, making them significantly older than the remaining patients (P = 0.006). Trauma sites included the craniofacial regions in 10 patients and the lumbar spine and pelvis in one patient each. At the time of trauma, six patients had a bump at the site, whereas none had extradural hematomas or bone fractures. The median time from trauma to onset was 4 weeks. Of these 12 patients, three had isolated bone (IB) disease; four had multifocal bone (MFB) disease, including the bone lesion at the trauma site; and five had multisystem disease, including four with lesions in neighboring tissue and one with polyuria (posterior pituitary lesion) more than 1 year before the trauma-triggered bone lesion. Treatment responses were good in all 12 patients and none died, but relapses were observed in two patients, one each with IB and MFB disease. CONCLUSIONS: About 5% of pediatric patients with LCH developed new trauma-triggered bone lesions at a relatively old age. These lesions can manifest as IB, or, in patients with underlying LCH diseases, as MFB or multisystem. Good clinical outcomes were observed in these patients.

[Chronic kidney disease - Mineral bone disorders: Physiopathology and guidelines]. / Troubles minéraux et osseux dans la maladie rénale chronique : physiopathologie, conséquences et prise en charge.

Chronic Kidney Disease (CKD) is associated with a strong impact on phosphocalcic homeostasis, due to the chronic reduction in glomerular filtration rate (GFR) (phosphate excretion decrease), the inhibition of calcitriol synthesis and dietary restrictions. CKD-Mineral and Bone Disorders (CKD-MBD) must be monitored in CKD patients with biological work-up associated with bone markers and bone density dual X-ray absorptiometry. Adapted diet (phosphate restriction, normalization of calcium intake) and medications (vitamin D, phosphate binders, calcimimetics) help to correct CKD-MBD. Serum parathormone must be kept between 2 to 9 times the usual values, to limit renal osteodystrophy and avoid tertiary hyperparathyroidism. CKD patients are also at risk of artery calcifications, which can significantly increase the morbidity and mortality of the affection. Bisphosphonates may be used after correction of biological abnormalities, in patients with estimated GFR above 30ml/min/1,73m2. Even if transplantation aims to normalize kidney function, kidney transplant recipients remain at risk of CKD-MBD. Biology and bone density dual X-ray absorptiometry must be regularly assessed, especially in the few months following the transplantation. More studies are needed to know if treatments of CKD-MBD are well tolerated in severe CKD and if they are associated with a decrease of bone fracture and vascular calcifications.

A comprehensive review on endemic and experimental fluorosis in sheep: Its diverse effects and prevention.

Fluoride is a natural element widely distributed in the environment and plays an important role in the growth of humans and animals. However, in many species, high concentrations of fluoride induce several problems, such as dental, skeletal, and non-skeletal fluorosis. Sheep living in endemic areas are sensitive to the chronic toxicity of fluoride, and they have been found to suffer not only from teeth and bone problems but also from other organs. Studies indicating the chronic harmful effects of fluoride on teeth, bones, blood biochemical parameters, kidney, liver, heart, reproductive system and growth in sheep have been clearly summarized in this review. Besides, this work also includes updated progress in terms of prevention or reduction of fluoride toxicity in this species.

Systemic cystic angiomatosis mimicking metastatic cancer.

BACKGROUND: Cystic angiomatosis is a rare benign disease presents with multiple lytic and sclerotic bone lesions mimicking a metastatic malignant neoplasia with less than 50 cases have been reported in literature so far. CASE PRESENTATION: We reported a case of a 48-year-old woman who presented to an oncology clinic with multiple lytic and sclerotic bone lesions. Oncologic investigation for metastatic malignant neoplasia started. After that the negative results were obtained by evaluating the primary tumor site, a final diagnosis of cystic angiomatosis was made according to bone biopsy results. CONCLUSIONS: Cystic angiomatosis is a rare disease with unpredictable prognosis. It can mimic metastatic malignancy especially when it presents at old age.

Analysis of Tertiary Hospital Utilization in Pediatric Orthopaedics: a Study Using Nationwide Sample Data from Korea.

BACKGROUND: In the Korean medical system, the severity classification for a specific disease depends primarily on its nationwide admission rate in tertiary hospitals. Inversely, one of the important designation criteria for a tertiary hospital is the hospital's treatment ratio of patients classified as having a specific severe disease. Most diseases requiring pediatric orthopaedic surgery (POS) are not currently classified as high severity in terms of disease severity. We investigated the admission rates for the representative POS diseases in tertiary hospitals and compared these rates with those for adult orthopaedic surgery (AOS) diseases. METHODS: Seven POS diagnoses and three AOS diagnoses were selected based on frequency of admission. Nationwide sample data were used to investigate the admission rates for these representative diagnoses from 2008 to 2017. RESULTS: Six of the seven frequent POS diagnoses presented high admission rates in tertiary hospitals (62.5-92.3%). In contrast, all frequent AOS diagnoses presented low admission rates in tertiary hospitals. CONCLUSION: The admission rates of frequent POS diagnoses in tertiary hospitals are high. Considering that these rates are the most important factors for the classification of disease severity, POS diseases seem to be underestimated in terms of severity. This may lead to a tendency for tertiary hospitals to intentionally reduce the admission of children with POS diseases. As a result, these children may not receive appropriate professional care. Therefore, for the disease severity, POS diseases should be classified differently from general AOS diseases by using different criteria reflecting the patient's age.

18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications.

In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to the early cellular changes that precede gross pathological findings, often leading to delayed disease diagnoses and suboptimal therapeutic strategies. 18F-sodium fluoride (18F-NaF)-positron emission tomography (PET) is an emerging imaging modality with the potential for early diagnosis and monitoring of bone diseases through the detection of subtle metabolic changes. Specifically, the dissociated 18F- is incorporated into hydroxyapatite, and its uptake reflects osteoblastic activity and bone perfusion, allowing for the quantification of bone turnover. While 18F-NaF-PET has traditionally been used to detect metastatic bone disease, recent literature corroborates the use of 18F-NaF-PET in benign osseous conditions as well. In this review, we discuss the cellular mechanisms of 18F-NaF-PET and examine recent findings on its clinical application in diverse metabolic, autoimmune, and osteogenic bone disorders.

Harmine Alleviates Titanium Particle-Induced Inflammatory Bone Destruction by Immunomodulatory Effect on the Macrophage Polarization and Subsequent Osteogenic Differentiation.

Peri-prosthetic osteolysis (PPO) and following aseptic loosening are regarded as the prime reasons for implant failure after joint replacement. Increasing evidence indicated that wear-debris-irritated inflammatory response and macrophage polarization state play essential roles in this osteolytic process. Harmine, a ß-carboline alkaloid primitively extracted from the Peganum harmala seeds, has been reported to have various pharmacological effects on monoamine oxidase action, insulin intake, vasodilatation and central nervous systems. However, the impact of harmine on debris-induced osteolysis has not been demonstrated, and whether harmine participates in regulating macrophage polarization and subsequent osteogenic differentiation in particle-irritated osteolysis remains unknown. In the present study, we investigated the effect of harmine on titanium (Ti) particle-induced osteolysis in vivo and in vitro. The results suggested harmine notably alleviated Ti particle-induced bone resorption in a murine PPO model. Harmine was also found to suppress the particle-induced inflammatory response and shift the polarization of macrophages from M1 phenotypes to M2 phenotypes in vivo and in vitro, which improved anti-inflammatory and bone-related cytokines levels. In the conditioned medium from Ti particle-stimulated murine macrophage RAW264.7 cells treated with harmine, the osteoblast differentiation ability of mouse pre-osteoblastic MC3T3-E1 cells was greatly increased. And we also provided evidences that the immunomodulatory capacity of harmine might be attributed to the inhibition of the c-Jun N-terminal kinase (JNK) in wear particle-treated macrophages. All the results strongly show that harmine might be a promising therapeutic agent to treat PPO.

Smart Cargo Delivery System based on Mesoporous Nanoparticles for Bone Disease Diagnosis and Treatment.

Bone diseases constitute a major issue for modern societies as a consequence of progressive aging. Advantages such as open mesoporous channel, high specific surface area, ease of surface modification, and multifunctional integration are the driving forces for the application of mesoporous nanoparticles (MNs) in bone disease diagnosis and treatment. To achieve better therapeutic effects, it is necessary to understand the properties of MNs and cargo delivery mechanisms, which are the foundation and key in the design of MNs. The main types and characteristics of MNs for bone regeneration, such as mesoporous silica (mSiO2 ), mesoporous hydroxyapatite (mHAP), mesoporous calcium phosphates (mCaPs) are introduced. Additionally, the relationship between the cargo release mechanisms and bone regeneration of MNs-based nanocarriers is elucidated in detail. Particularly, MNs-based smart cargo transport strategies such as sustained cargo release, stimuli-responsive (e.g., pH, photo, ultrasound, and multi-stimuli) controllable delivery, and specific bone-targeted therapy for bone disease diagnosis and treatment are analyzed and discussed in depth. Lastly, the conclusions and outlook about the design and development of MNs-based cargo delivery systems in diagnosis and treatment for bone tissue engineering are provided to inspire new ideas and attract researchers' attention from multidisciplinary areas spanning chemistry, materials science, and biomedicine.

Rapidly destructive coxopathy due to dialysis amyloidosis: a case report.

Rapidly destructive coxopathy (RDC) is a disease that is sometimes seen in geriatric patients. A total hip arthroplasty (THA) is mostly chosen to treat the RDC, but few cases are known that received THAs due to RDC associated with dialysis amyloidosis. We report a case of RDC due to dialysis amyloidosis with special references to its pathophysiology. The case involved a 61-year-old male who had been on dialysis for seven years due to diabetic nephropathy. At his first visit, the radiographs showed collapse and flattening of the femoral head, which progressed within a month. Magnetic resonance imaging for the hip disclosed bone marrow edoema of the acetabulum and sclerosis of the subchondral bone of the femoral head. Biochemical analyses for the blood revealed high inflammatory reactions with elevated C-reactive protein and white blood cell count, but the joint fluid cultures were negative for general bacteria, tubercle bacillus, and nontuberculous mycobacteria. As he did not have gastrointestinal disorders or inflammatory arthritis other than the left hip and no disease that caused elevated inflammatory reactions was observed, we diagnosed the patient with RDC due to dialysis amyloidosis, and a THA was performed. Pathological findings for the synovium collected during surgery showed infiltration of the inflammatory mononuclear cells and vascular hyperplasia. The synovial tissues were extensively stained with an antibody to ß2-microglobulin. Many tartrate-resistant acid phosphatase-positive multinucleated cells were also observed in the synovium. One year after surgery, his left hip pain disappeared and he returned to work.

The molecular structure and role of CCL2 (MCP-1) and C-C chemokine receptor CCR2 in skeletal biology and diseases.

Monocyte chemoattractant protein-1, also called chemokine (C-C motif) ligand 2 (CCL2) or small inducible cytokine A2, is an inflammatory mediator capable of recruiting monocytes, memory T cells, and dendritic cells. CCL2 is a member of the CC chemokine superfamily, which binds to its receptor, C-C motif chemokine receptor-2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx. It exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases. This review discusses the molecular structure and role of CCL2 and CCR2 in skeletal biology and disease. Molecular structure analyses reveal that CCL2 shares a conserved C-C motif; however, it has only limited sequence homology with other CCL family members. Likewise, CCR2, as a member of the G-protein-coupled seven-transmembrane receptor superfamily, shares conserved cysteine residues, but exhibits very limited sequence homology with other CCR family members. In the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone-related peptide, interleukin 1b, tumor necrosis factor-α and transforming growth factor-beta, RANKL, and mechanical forces. The interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF-κB, PI3K/MAPKs, and JAK/STAT-1/STAT-3. Understanding the role of CCL2 and CCR2 will facilitate the development of novel therapies for skeletal disorders, including rheumatoid arthritis, osteolysis and other inflammatory diseases related to abnormal chemotaxis.

Bone sporotrichosis: 41 cases from a reference hospital in Rio de Janeiro, Brazil.

BACKGROUND: Bone sporotrichosis is rare. The metropolitan region of Rio de Janeiro is hyperendemic for zoonotic sporotrichosis and the bone presentations are increasing. METHODS: We studied a retrospective cohort of 41 cases of bone sporotrichosis, diagnosed from 1999-2016. The inclusion criteria was fungal culture isolation from any clinical specimen associated to bone involvement (radiography and/or computed tomography) compatible with fungal osteomyelitis or histopathological findings of bone material compatible with sporotrichosis. Molecular identification was performed when possible. RESULTS: Male patients represented 58.5% of the cases, with a cohort median age of 43 years. Immunosuppressive conditions were present in 68.3% of the patients, mostly HIV coinfection (51.2%). Multifocal bone involvement (more than one anatomical segment) was diagnosed in 61% of the patients, while 39% presented unifocal involvement. The bones of the hands were the most affected (58.5%), followed by the feet (41.5%) and tibia (26.8%). Multifocal group was characterized by a higher proportion of males (p = 0.0045) with immunosuppressive conditions (p = 0.0014). Amphotericin B followed by oral itraconazole was the main treatment, with a median time of 16.7 months (1.5 to 99.2 months), and cure of 53.7% of the patients (84.6% of immunocompetent and 39.3% of immunocompromised patients). Sequelae occurred in 12.2% of the patients-amputations (7.3%) and ankylosis (4.9%), while 22% died in the course of the disease. Sporothrix brasiliensis was the causative agent in all the 9 (22%) performed cases. CONCLUSIONS: Bone sporotrichosis is a chronic, challenging condition with prolonged treatment, often with poor results and sequelae.

Percutaneous Treatment of Bone Hydatid Cyst.

Cystic echinococcosis (CE) may be encountered in almost every site of the body, but bone involvement is relatively rare. The vertebral column and pelvis are the most affected areas. The combined medical and surgical approach is the main treatment option in current literature. Although percutaneous treatment of CE cysts located in the liver, spleen, kidney, and soft tissues has become a serious alternative to surgery, there is no bone CE cyst treated percutaneously in the literature. This case report aims to point out that percutaneous treatment can be an effective treatment choice and alternative to surgery.