Solanum muricatum Ameliorates the Symptoms of Osteogenesis Imperfecta In Vivo.

Pepino (Solanum muricatum), which is an evergreen plant native to South America, is well-known for its effects in antioxidation, antidiabetic activity, anti-inflammation, and antitumor activity. A previous study in our lab indicated that Solanum muricatum (SM) extract promoted osteogenic differentiation by upregulating Wnt and BMP signaling pathway in rat bone marrow stromal cells. The osteogenesis imperfecta (OI) mouse model was used in order to further discover the osteogenic properties of SM extract in the present research. We utilized microCT analysis to collect bone mass and microarchitectural parameters at vertebrae and at femur metaphysis in OI mice. Raman spectrometry was applied to identify change of bone mineral and matrix composition during SM treatment. Finally, collagen synthesis marker PINP and collagen degradation marker CTX were detected using enzyme immunoassay. SM extract could improve the bone mass and microarchitectural parameters both at vertebrae and at femur metaphysis. It also significantly increased the collagen content by promoting its biosynthesis and inhibiting its degradation. By using heterozygous Col1a1Jrt /+ mice as a model of OI, 6 weeks treatment of SM extract could significantly ameliorate the symptoms in OI mice. Thus, SM holds potential for developing new drugs of bone formation and bone remodeling.

WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts.

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.

De la osteología a la osteomiología: tres décadas de aportes originales continuos al análisis biomecánico osteomuscular / From osteology to osteo-myology: three decades of continuous, original contributions to musculoskeletal biomechanical analysis

En consonancia con la orientación tradicional de nuestras investigaciones, la Osteología está incorporando progresivamente el análisis estructural-biomecánico óseo y las interacciones músculo-esqueléticas. En este artículo se sintetizan los aportes originales del CEMFoC a la Osteología moderna en el terreno biomecánico en forma didáctica, para que el lector aprecie sus posibles aplicaciones clínicas. Los hallazgos aportaron evidencias sucesivas en apoyo de dos proposiciones fundamentales: a) los huesos deben interpretarse como estructuras resistivas, biológicamente servocontroladas ("Los huesos tienden siempre a mantener un factor de seguridad que permite al cuerpo trabajar normalmente sin fracturarse" ­ Paradigma de Utah) y b) los huesos interactúan con su entorno mecánico, determinado principalmente por las contracciones musculares, en forma subordinada al entorno metabólico ("Los huesos son lo que los músculos quieren que sean, siempre que las hormonas lo permitan"). Los avances producidos se refieren, tanto cronológica como didácticamente, al conocimiento osteológico en general y al desarrollo de recursos novedosos para el diagnóstico no invasivo de fragilidad ósea, para distinguir entre osteopenias y osteoporosis, y para discriminar entre sus etiologías 'mecánica' y 'sistémica'. Finalmente, el nuevo conocimiento se integra en la proposición de un algoritmo diagnóstico para osteopenias y osteoporosis. El espíritu general de la presentación destaca que la evaluación osteomuscular dinámicamente integrada genera un nuevo espacio de análisis personalizado de los pacientes para la atención de cualquier osteopatía fragilizante con criterio biomecánico. (AU)

In consonance with the traditional spirit of our studies, skeletal research is being progressively focused on the structural-biomechanical analysis of bone and the muscle-bone interactions. In this article, the CEMFoC's members summarize their original findings in bone biomechanics and their potential clinical applications. These findings provided evidence supporting two fundamental hypotheses, namely, A. bones constitute resistive structures, which are biologically servo-controlled ('Bones tend to maintain a safety factor which allows the body to function normally avoiding fractures' ­ the 'Utah paradigm'), and B. the interactions of bones with their mechanical environment mainly are determined by the contraction of local muscles - 'bone-muscle units'), and are subordinated to the control of the metabolic environment ('Bones are what muscles wish them to be, provided that hormones allow for it'). The achievements in the field are presented in a chronological and didactical sequence concerning the general knowledge in Osteology and the development of novel resources for non-invasive diagnosis of bone fragility, aiming to distinguish between osteopenias and osteoporosis and the 'mechanical' and 'metabolic' etiology of these conditions. Finally, the integrated new knowledge is presented as supporting for a proposed diagnostic algorithm for osteopenias and osteoporosis. In general terms, the article highlights the dynamic evaluation of the musculoskeletal system as a whole, opening a new diagnostic field for a personalized evaluation of the patients affected by a boneweakening disease, based on functional and biomechanical criteria. (AU)

A novel variant of osteogenesis imperfecta type IV and low serum phosphorus level caused by a Val94Asp mutation in COL1A1.

Osteogenesis imperfecta (OI) is a rare congenital disorder characterized by bone fragility and fractures, and associated with bone deformity, short stature, dentin, ligament and blue­gray eye sclera. OI is caused by a heterozygous mutation in collagen α­1(I) chain (COL1A1) or collagen α­2(I) chain (COL1A2) genes that encode α chains of type I collagen. Collagen α chain peptide contains an N­propeptide, which has a role in assembly and processing of collagen. Point mutations in the N­propeptide domain appear to trigger OI. In the present study, a novel heterozygous missense mutation, c.281T>A (p.Val94Asp), was identified in the von Willebrand C domain of N­terminal of type I collagen in an individual with type IV OI. The majority of N­terminal mutations are associated with OI/Ehlers­Danlos syndrome (EDS); however, in the present study, the affected individual did not suffer from EDS and the level of serum phosphorus of the patient was low (0.67 mmol/l). A number of clinical phenotypes were observed at the same variation site or in the same region on the polypeptide chain of COL1A, which suggests that additional genetic and environmental factors may influence the severity of OI. The present study may provide insight into the phenotype­genotype association in collagen-associated diseases and improve clinical diagnosis of OI.

A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5'-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and their roles in bone mineralization.

Osteogenesis imperfecta and pneumatization of bone-- a hidden reality.

Osteogenesis imperfecta is a bone disorder in which three factors that influence bone strength (quality, mass, and geometry of osseous tissue) are affected. Pneumatization refers to the development of air-filled cavities inside the bone. Knowledge about these air-filled cavities provides valuable information for understanding the diagnosis and spread of various pathologic entities like hemangiomas, giant cell tumors, eosinophilic granulomas, and even metastatic tumor deposits. This paper presents a case in which radiologic, clinical, biochemical, and karyotypic evaluations lead to a diagnosis of osteogenesis imperfecta.

New trends in the treatment of osteogenesis imperfecta type III - own experience.

INTRODUCTION: Osteogenesis imperfecta (OI) is a genetic disorder caused by a mutation in the genes that encode the chains of type I collagen. Clinical manifestations include increased bone fragility and blue sclerae. OI type III is the most severe form with fractures occurring already in utero. Fracture immobilisation and orthopaedic surgery are the mainstay of treatment for patients with OI, and are combined with rehabilitation and bisphosphonate therapy. PATIENTS AND METHODS: The study involved 8 children with osteogenesis imperfecta type III, aged 1 month to 6 years. All of them were treated with cyclic intravenous infusions of pamidronate. Laboratory studies conducted before and after each 3-day cycle of pamidronate therapy included complete blood count, serum calcium, phosphorus, magnesium, osteocalcin, and calcium/creatinine index in morning urine and collagen type I cross-linked N-telopeptide (NTx). Infant total body densitometric scans were obtained in 5/8 patients. RESULTS: Patients were treated for periods of 3-58 months. Fracture rates decreased with treatment in all patients compared to the prenatal period. Pamidronate also slowed down bone turnover, and particularly the resorption rate. The most common side effects during treatment included hypocalcaemia (7/8 patients) and fever (up to 39 degrees C) after the first cycle of treatment. CONCLUSION: Symptomatic bisphosphonate therapy in children with osteogenesis imperfecta ameliorated the clinical course (decreased bone pain and reduced incidence of fractures). Pamidronate therapy had a positive impact on functional parameters such as independence in everyday activities and better mobility. The treatment was safe.

Oim mice exhibit altered femur and incisor mineral composition and decreased bone mineral density.

To investigate the role of the pro alpha 2(I) collagen chains of type I collagen in mineralization we used the oim (osteogenesis imperfecta model) mouse as our model system. The oim/oim mouse (homozygous for a null mutation in its COL1A2 gene of type I collagen) fails to synthesize functional pro alpha 2(I) collagen chains, synthesizing only homotrimers of pro alpha 1(I) collagen chains. To evaluate the role of pro alpha 2(I) collagen in type I collagen structure/function in mineralized tissues, we examined age-matched oim/oim, heterozygous (oim/+), and wild-type (+/+) mouse femurs and incisors for mineral composition (calcium, phosphorus, magnesium, fluoride, sodium, potassium, and chloride) by neutron activation analyses (NAA), and bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) in a longitudinal study (7 weeks to 16 months of age). NAA demonstrated that oim/oim femurs had significant differences in magnesium, fluoride, and sodium content as compared with +/+ mouse femurs, and oim/oim teeth had significant differences in magnesium content as compared to +/+ teeth. The ratio of calcium to phosphate was also significantly reduced in the oim/oim mouse femurs (1.58 +/- 0.01) compared with +/+ femurs (1.63 +/- 0.01). DEXA demonstrated that oim/oim mice had significantly reduced BMC and BMD as compared to oim/+ and +/+ mice. Serum and urine calcium, magnesium, and phosphorus levels, and Ca(47) absorption across the gut were equivalent in oim/oim and +/+ mice, with no evidence of hypercalciuria. These studies suggest that the known decreased biomechanical properties of oim/oim bone reflect both altered mineral composition as well as the decreased BMD, which further suggests that the presence of alpha2(I) chains plays an important role in mineralization.