A CREB1-miR-181a-5p loop regulates the pathophysiologic features of bone marrow stromal cells in fibrous dysplasia of bone.

BACKGROUND: Fibrous dysplasia (FD) is a bone marrow stromal cell (BMSC) disease caused by activating mutations of guanine nucleotide-binding protein alpha-stimulating activity polypeptide (GNAS) and is characterized by increased proliferative activity and disrupted osteogenesis of BMSCs. However, the molecular mechanisms regulating the pathophysiologic features of BMSCs in FD remain unknown. This study aimed to identify and verify the roles of the CREB1-miR-181a-5p regulatory loop in FD pathophysiology. METHODS: MicroRNA (miRNA) sequencing analysis was used to identify the possible miRNAs implicated in FD. The proliferation, apoptosis, and osteogenic differentiation of BMSCs, as well as the osteoclast-induced phenotype, were measured and compared after exogenous miR-181a-5p transfection into FD BMSCs or miR-181a-5p inhibitor transfection into normal BMSCs. Chromatin immunoprecipitation and luciferase reporter assays were performed to verify the interactions between CREB1 and miR-181a-5p and their effects on the FD pathological phenotype. RESULTS: Compared to normal BMSCs, FD BMSCs showed decreased miR-181a-5p levels and exhibited increased proliferative activity, decreased apoptotic capacity, and impaired osteogenesis. FD BMSCs also showed a stronger osteoclast activation effect. miR-181a-5p overexpression reversed the pathophysiologic features of FD BMSCs, whereas miR-181a-5p suppression induced an FD-like phenotype in normal BMSCs. Mechanistically, miR-181a-5p was the downstream target of CREB1, and CREB1 was posttranscriptionally regulated by miR-181a-5p. CONCLUSIONS: Our study identifies that the interaction loop between CREB1 and miR-181a-5p plays a crucial role in regulating the pathophysiologic features of FD BMSCs. MiR-181a-5p may be a potential therapeutic target for the treatment of FD.

Nuevos avances en el conocimiento de la historia natural de la displasia fibrosa / News advances in the knowledge of natural history of the fibrous dysplasia

La displasia fibrosa (DF) es una enfermedad infrecuente del hueso, no hereditaria, producida por una mutación activadora del gen GNAS, responsable de codificar la unidad a-estimuladora de la proteína G (Gsa). La presentación clínica de la enfermedad es muy variada, pues adopta desde formas asintomáticas hasta otras marcadamente sintomáticas. En los últimos años, el análisis exhaustivo de bases de datos de pacientes con DF ha permitido conocer más sobre su historia natural. En este artículo se revisa la información actualmente disponible sobre algunos aspectos que ayudarán al mejor enfoque clínico del paciente, como son: la utilidad clínica de los marcadores óseos, los factores pronósticos para el desarrollo de fracturas, la DF como condición predisponente para el desarrollo de tumores específicos, nuevas perspectivas sobre la fisiopatología del dolor óseo y nuevas estrategias terapéuticas. Un mayor conocimiento sobre la historia natural de esta enfermedad finalmente redundará en la mejor calidad de vida de los pacientes con DF. (AU)

Fibrous dysplasia (FD) is an infrequent, non-hereditary bone disease caused by a somatic mutation of the GNAS gene, responsible for encoding the a-subunit of the G-protein (Gsa). The clinical presentation of the disease varies greatly, with some patients being asymptomatic and others markedly symptomatic. The exhaustive analysis of the database from patients with FD has allowed to learn more about the natural history of this disease. This article reviews the current information available on the clinical utility of bone markers, the prognostic factors for the occurrence of fractures, the evidence supporting as a predisposing condition for the development of specific tumors, new perspectives on the pathophysiology of bone pain, and emerging therapeutic strategies. A greater understanding of the natural history of this disease will allow to make better medical decisions, which will ultimately contribute to improve FD patients' quality of life. (AU)

Displasia fibrosa ósea / Fibrous dysplasia of bone

La displasia fibrosa ósea es un trastorno no hereditario del desarrollo esquelético caracterizado por una proliferación anormal de fibroblastos y diferenciación deficiente de osteoblastos que conduce a un reemplazo del tejido óseo esponjoso por tejido conectivo fibroso. Es producida por una mutación somática activadora del gen GNAS1 que induce una activación y proliferación de células mesenquimales indiferenciadas con formación de tejido fibroso y trabéculas óseas anómalas. Existen formas monostóticas, poliostóticas y craneofaciales con diversos grados de dolor, deformidades y fracturas óseas, aunque muchos casos son asintomáticos. En ocasiones se producen quistes óseos aneurismáticos, hemorragias, compromisos neurológicos y raramente osteosarcomas. Algunos casos se asocian a síndrome de McCune-Albright, síndrome de Mazabraud y a osteomalacia por hipofosfatemia por pérdida tubular renal inducida por el FGF23 producido por el tejido displásico. Los hallazgos en las radiografías convencionales son característicos, aunque variables y de carácter evolutivo. La gammagrafía ósea es la técnica de imagen con mayor sensibilidad para determinar la extensión de la enfermedad. El diagnóstico diferencial incluye múltiples lesiones óseas de características similares y en raras ocasiones se requiere biopsia ósea o estudio genético para confirmarlo. No existe un consenso unánime acerca del abordaje terapéutico de estos pacientes, razón por la cual es necesario un enfoque multidisciplinario. La conducta puede ser expectante o quirúrgica según el tipo de lesiones y es importante el manejo del dolor y de las endocrinopatías asociadas. La mayor experiencia publicada se refiere al uso de bifosfonatos y, más recientemente, denosumab. Los tratamientos actuales son insuficientes para modificar el curso de la enfermedad y es necesario el desarrollo de nuevas moléculas que actúen específicamente en el gen GNAS1 o sobre las células mesenquimales afectadas. (AU)

Fibrous dysplasia of bone is a noninherited developmental anomaly of bone characterized by abnormal proliferation of fibroblasts and differentiation of osteoblasts that cause a replacement of trabeculous bone by fibrous connective tissue. It is caused by a somatic mutation in the GNAS1 gene, which induces an undifferentiated mesenquimal cells activation and proliferation with formation of fibrous tissue and abnormal osseous trabeculae. There are monostotic, polyostotic and craniofacial variants with different grades of bone pain, deformities and fractures, although many cases remain asymptomatic. Aneurysmal bone cysts, bleeding, neurological compromise and infrequently osteosarcoma are possible complications. Some cases are associated to McCune-Albright syndrome, Mazabraud syndrome or hypophosphatemia and osteomalacia due to to renal tubular loss induced by FGF23 produced by dysplastic tissue. The findings on conventional radiography are characteristic although variable and evlolve with time. Bone scintigraphy is the most sensitive technique to evaluate the extent of disease. Differential diagnosis include several osseous lesions of similar appearance and, in some cases, bone biopsy or genetic testing may be necessary. Today, there is no consensus regarding the therapeutic approach for these patients and it is necessary a multidisciplinary medical team. Watchful waiting or surgical interventions can be indicated, depending on the type of bone lesions. Bone pain and associated endocrinopathies management are very important. Most published experience refers to the use of bisphosphonates and, more recently, denosumab. Current treatments are insufficient to modify the natural curse of the disease and therefore, new molecules with specific action on GNAS1 gene or affected mesenchymal cells are necessary. (AU)

Nueva variante patogénica en el gen NPR2: etiología de talla baja, macrocefalia y displasia ósea en varón afectado de displasia acromesomélica tipo Maroteaux / New pathogenic variant in the NPR2 gene: Etiology of low size, macrocephaly and bone dysplasia in a male with acromesomelic dysplasia Maroteaux-type

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Fibrous dysplasia.

Fibrous dysplasia is an uncommon bone disease. The diagnosis is usually not difficult, given the symptoms, radiology, and histology. The gene involved is the α subunit of the G-protein receptor. Recent innovation in molecular pathology has helped us understand the mechanism of disease pathogenesis. The treatment of fibrous dysplasia is limited to maintenance of maximum bone density. Surgical reinforcement is used to treat bowing deformities and fractures as they occur. Malignant transformation of fibrous dysplasia is rare. Currently, there is no therapy for preventing the disease from advancing or for malignant transformation.

Displasia fibrosa craniomaxilofacial: relato de caso / Craniomaxilofacial fibrous dysplasia: case report

A displasia fibrosa é uma condição patológica benigna onde ocorre a proliferação e substituição do tecido ósseo por tecido fibroso. Existem duas categorias primárias da doença: displasia fibrosa monostótica, que envolve somente um osso, e displasia fibrosa poliostótica, que acomete múltiplos ossos, ocorrendo mais frequentemente no esqueleto crânio-facial. Geralmente esta condição patológica tem início na infância e progride até a puberdade e adolescência, podendo estar relacionada com a chamada Síndrome de McCune-Albright. Neste trabalho, realizou-se uma revisão de literatura a apresenta-se um caso clínico, enfocando os aaspectos etiológicos, clínicos, imaginológicos e o respectivo tratamento da displasia fibrosa crânio-facial.

Surgical treatment of dysplasia fibrosa and defectus fibrosus with bone allografts.

BACKGROUND: A common feature of dysplasia fibrosa and defectus fibrosus is the development of foci of disordered fibrous tissue in bone that tend to grow and displace regular bone tissue. The objective of this study was to evaluate the efficacy of surgical treatment with bone allografts in patients with fibrous dysplasia and fibrous defect of bone. MATERIAL AND METHODS: The study group consisted of 99 patients aged from 9 to 58 years (mean age 22 years), including 56 men and 43 women. A total of 145 surgical procedures were performed in this group at the Bone Tumour and Neoplasm Unit between 1999 and 2005. In all cases histopathological verification confirmed fibrous dysplasia or fibrous defect of bone. The follow-up period was from 1 to 5 years (mean 2.5 years). RESULTS: In 85 patients there were no recurrences. A total of 96 surgical procedures were performed in this group. The other 14 patients experienced recurrences and no graft remodelling. Forty-nine surgical procedures were performed in this group because of multiple (from 2 to 6) relapses of the tumours. CONCLUSIONS: 1. Resection surgery and filling the defect with bone graft in the basic tyep of treatment in fibrous dysplasia and bibrous defect of bone and leads to good outcomes. 2. Frozen cortico-cancelleous allografts are well incorporated and bone remodeling is not assocaited with inflammatory complications, resulting into good outcomes of the operative treatment.

The nature of fibrous dysplasia.

Fibrous dysplasia has been regarded as a developmental skeletal disorder characterized by replacement of normal bone with benign cellular fibrous connective tissue. It has now become evident that fibrous dysplasia is a genetic disease caused by somatic activating mutation of the Gsalpha subunit of G protein-coupled receptor resulting in upregulation of cAMP. This leads to defects in differentiation of osteoblasts with subsequent production of abnormal bone in an abundant fibrous stroma. In addition there is an increased production of IL-6 by mutated stromal fibrous dysplastic cells that induce osteoclastic bone resorption.

[Fibrous dysplasia]. / Fibröse Dysplasie.

Fibrous dysplasia is a tumorlike, benign lesion, caused by sporadic mutation during early embryogenesis. The skeletal involvement becomes increasingly visible during growth. The number and extent of dysplastic lesions increase until the age of 15. The polyostotic form is often associated with endocrine dysfunction, which should be diagnosed and treated early. Malignant transformation of fibrous dysplastic lesions is less than 1%; therefore, treatment or resection of the lesion itself is not necessary. The progress of the lesions during growth can lead to pain, fractures, and deformities. Bisphosphonates are effective for pain relief, but have no assured effect on the natural history of the disease. Fracture healing is not compromised by the disease. Conservative treatment with casts is therefore effective, especially for the upper limbs. The surgical approach with deformity correction and stabilization remains challenging particularly with regard to the proximal femur. Intramedullary devices should be preferred to plates, if possible.

Tratamiento de la displasia fibrosa asociada a hemofilia C: a propósito de un caso / Treatment for fibrous dysplasia when associated with hemophilia C: A case report

La displasia fibrosa es una enfermedad ósea benigna que cambiael tejido óseo normal por una proliferación de tejido conectivo. Se piensaque la alteración del gen Gsα es la principal razón de la enfermedad.La hemofilia C es una enfermedad sanguínea, hereditaria rara, que provocahemorragias en pacientes afectos. Es autonómica recesiva, por lo quehombres y mujeres pueden estar afectos.Paciente de 13 años que desarrolla una displasia fibrosa en maxilar superiorderecho que empieza con dolor durante la masticación de alimentosduros. Presenta abombamiento de vestíbulo y enrojecimiento de paladarderecho.Presenta un déficit discreto de factor XI (heterocigoto). Por ello, necesitauna preparación especial antes de extirpar la lesión debido a su déficit.Se ha descubierto que la razón de la displasia fibrosa es la mutación delgen Gsα (GNAS1) que está en el cromosoma 20q.La causa de la hemofilia C es el déficit del factor XI debido a una mutacióndel gen FXI en el cromosoma 4. Quizás estas dos raras enfermedades tenganuna relación, porque ambas se presentan en el mismo paciente(AU)

Fibrous Dysplasia is a benign bone disease that changesnormal bone tissue for a proliferation of connective fibrous tissue.It is thought that an alteration of the Gsα gene is the main causeof the disease.Hemophilia C is a rare inherited blood disease leading to abnormalhemorrhages in affected patients. They have a factor XI deficiency.It is the least frequent of all hemophilias. It is a recessive autosomaldisease, affecting both men and women.A 13 year-old patient developed fibrous dysplasia in right uppermaxilla. The patient started with pain on chewing hard food. Shehad vestibular swelling and reddening of the right side of the palate.She had a discrete factor XI deficiency (heterozygotic). She neededspecial preparation before the lesion could be removed because ofher deficiency.It has been discovered that the mutation of gene Gsα (GNAS1) isthe reason for fibrous dysplasia. This gene is in chromosome 20q.The cause of hemophilia C is a factor XI deficiency due to a mutationin the FXI gene in chromosome 4. Perhaps these two rare diseasesare related, because both are unusual diseases and both are in thesame patient(AU)

Fibrous dysplasia, phosphate wasting and fibroblast growth factor 23.

Fibrous dysplasia (FD) is a classic feature of McCune-Albright syndrome (MAS). Renal phosphate wasting commonly occurs in FD, contributing to the mineralization defect in FD lesions and in non-FD bones, potentially increasing bone deformity. The presence of phosphate wasting correlates with measures of FD disease activity. Hypophosphatemia and phosphate wasting in FD are accompanied by inappropriately normal or low 1,25-dihydroxyvitamin D3 concentrations, similar to X-linked hypophosphatemic rickets. Recently, fibroblast growth factor 23 (FGF23) has emerged as an important humoral factor regulating phosphate and vitamin D homeostasis. FGF23 inhibits renal tubular phosphate reabsorption and decreases 1,25-dihydroxyvitamin D3. Interestingly, FGF23 is produced by normal osteoblasts as well as the abnormal osteogenic precursors present in FD lesions. However, FD lesions likely produce FGF23 in an unregulated fashion. Elevated circulating FGF23 correlates with total body FD disease burden and the presence of phosphate wasting. MAS mutations increase immature osteoblast lineage cells causing FD, resulting in dysregulated FGF23 production and, hence, phosphate wasting.

Bisphosphonate therapy for fibrous dysplasia.

Bony fibrous dysplasia is one of the hallmark features of McCune-Albright syndrome. Fibrous dysplasia can result in pain, fracture and deformity in affected areas. A number of observational, uncontrolled reports have been published outlining results of bisphosphonate therapy for fibrous dysplasia. Bisphosphonates are well tolerated and appear to be useful for reducing bone pain. Although their use is also associated with decreases in bone turnover, increases in bone density and radiological changes, their impact on the overall course of the disease, particularly the incidence of fractures and deformity, is less clear. Many questions remain about optimizing their use for fibrous dysplasia therapy.

Surgical management of fibrous dysplasia in McCune-Albright syndrome.

Polyostotic Fibrous Dysplasia associated with McCune-Albright Syndrome presents extreme challenges for the treating physician. The bone deformities, frequent fractures and weight bearing bone pain all combine to adversely affect the child's ability to engage in the normal activities of childhood. All too often the family is told that there is no real treatment for the bone disease. As a result of the rare nature of this syndrome, few orthopedic surgeons have had extensive experience with reconstructions for the skeletal deformities. Early surgery to address the upper femoral deformity and the innovative use of off-label internal fixation devices can have a profound effect on these young patients. The parents and patient must have a complete understanding of the effect of further growth on the reconstructions and be prepared to undergo repeated procedures as the deformities change and recur. Bone grafting and the use of common internal fixation devices (plates and screws) are almost always doomed to early failure. The innovative use of intramedullary devices can lead to prolonged ambulation and the eradication of weight bearing bone pain in selected patients. Frequent fractures and deformity can be effectively managed in most patients with these techniques.

McCune-Albright syndrome in adulthood.

The McCune-Albright syndrome is characterized by cafe-au-lait spots, precocious puberty and fibrous dysplasia. It is due to mutations in the gene encoding the Gs protein alpha subunit coupling 7-transmembrane-domain receptors to adenylate cyclase, leading to constitutive adenylate cyclase activation and cAMP overproduction. Endocrinologists, rheumatologists and gynecologists are confronted with new issues when these children reach adulthood. Dysplastic bone lesions seem to stabilize after puberty, but their disabling consequences (pain, fractures, etc.) may continue into adulthood. Gonadal function and fertility are often abnormal in women in whom puberty was precocious, owing to the persistence of a variable degree of ovarian autonomy that hinders adequate follicular development and ovulation. Acromegaly, when present, is often difficult to treat surgically because of skull-base dysplasia. Somatostatin analogs are only partially effective in most cases; fortunately, the GH receptor antagonist, pegvisomant may be more effective in normalizing IGF-I levels. Hyperthyroidism, generally due to multinodular toxic goiter, can be successfully treated by surgery or radioiodine administration. Recent data suggest that cancer incidence in adulthood (bone, breast, thyroid...) is increased in these patients.

Fibrous dysplasia. Pathophysiology, evaluation, and treatment.

Fibrous dysplasia is a common benign skeletal lesion that may involve one bone (monostotic) or multiple bones (polyostotic) and occurs throughout the skeleton with a predilection for the long bones, ribs, and craniofacial bones. The etiology of fibrous dysplasia has been linked to an activating mutation in the gene that encodes the alpha subunit of stimulatory G protein (G(s)alpha) located at 20q13.2-13.3. Most lesions are monostotic, asymptomatic, and identified incidentally and can be treated with clinical observation and patient education. Bisphosphonate therapy may help to improve function, decrease pain, and lower fracture risk in appropriately selected patients with fibrous dysplasia. Surgery is indicated for confirmatory biopsy, correction of deformity, prevention of pathologic fracture, and/or eradication of symptomatic lesions. The use of cortical grafts is preferred over cancellous grafts or bone-graft substitutes because of the superior physical qualities of remodeled cortical bone.