Van Buchem Disease: First Case Report from the Indian Subcontinent with an Early Presentation

Van Buchem disease is a rare autosomal recessive genetic disorder that causes a compromised inhibitory feedback mechanism resulting in increased bone formation and overgrowth of the skeleton leading to a variety of neurological symptoms. It has been reported in less than 50 patients most of which were in western Europe. We report the first case of this condition from the Indian subcontinent with an early presentation. This patient presented with a global delay in attaining the developmental milestones and progressive reduction in visual acuity and loss of hearing. He had dysmorphic facies, multiple cranial nerve palsies, and severe visual and auditory deficits. Imaging revealed sclerosing bone dysplasia. This case illustrates the clinical and imaging findings of this rare condition.

Looking for new anabolic treatment from rare diseases of bone formation

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterized by altered bone erosion or formation. In this review we will describe some bone formation-related disorders as Sclerosteosis, Van Buchem disease, Hypophosphatasia and Camurati-Engelmann disease. In the past decades the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

Molecular Basis for Craniofacial Phenotypes Caused by Sclerostin Deletion

Some genetic disorders are associated with distinctive facial features, which can aid in diagnosis. While considerable advances have been made in identifying causal genes, relatively little progress has been made toward understanding how a particular genotype results in a characteristic craniofacial phenotype. An example is sclerosteosis/van Buchem disease, which is caused by mutations in the Wnt inhibitor sclerostin (SOST). Affected patients have a high bone mass coupled with a distinctive appearance where the mandible is enlarged and the maxilla is foreshortened. Here, mice carrying a null mutation in Sost were analyzed using quantitative micro–computed tomographic (µCT) imaging and histomorphometric analyses to determine the extent to which the size and shape of craniofacial skeleton were altered. Sost−/− mice exhibited a significant increase in appositional bone growth, which increased the height and width of the mandible and reduced the diameters of foramina. In vivo fluorochrome labeling, histology, and immunohistochemical analyses indicated that excessive bone deposition in the premaxillary suture mesenchyme curtailed overall growth, leading to midfacial hypoplasia. The amount of bone extracellular matrix produced by Sost−/− cells was significantly increased; as a consequence, osteoid seams were evident throughout the facial skeleton. Collectively, these analyses revealed a remarkable fidelity between human characteristics of sclerosteosis/van Buchem disease and the Sost−/− phenotype and provide clues into the conserved role for sclerostin signaling in modulating craniofacial morphology.

Methylation of bone SOST impairs SP7, RUNX2, and ERα transactivation in patients with postmenopausal osteoporosis

Sclerostin (SOST), a glycoprotein predominantly secreted by bone tissue osteocytes, is an important regulator of bone formation, and loss of SOST results in Van Buchem disease. DNA methylation regulates SOST expression in human osteocytes, although the detailed underlying mechanisms remain unknown. In this study, we compared 12 patients with bone fractures and postmenopausal osteoporosis with eight patients without postmenopausal osteoporosis to understand the mechanisms via which SOST methylation affects osteoporosis. Serum and bone SOST expression was reduced in patients with osteoporosis. Bisulfite sequencing polymerase chain reaction revealed that the methylation rate was higher in patients with osteoporosis. We identified osterix (SP7), Runt-related transcription factor 2 (RUNX2), and estrogen receptor α (ERα) as candidate transcription factors activating SOST expression. Increased SOST methylation impaired the transactivation function of SP7, RUNX2, and ERα in MG-63 cells. AzadC treatment and SOST overexpression in MG-63 cells altered cell proliferation and apoptosis. Chromatin immunoprecipitation showed that higher methylation was associated with reduced SP7, RUNX2, and ERα binding to the SOST promoter in patients with osteoporosis. Our studies provide new insight into the role of SOST methylation in osteoporosis.

Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097

The secreted cystine-knot protein sclerostin was first identified from genetic screening of patients suffering from the rare bone-overgrowth diseases sclerosteosis and van Buchem disease. Sclerostin acts a negative regulator of bone growth through inhibiting the canonical Wnt signalling cascade by binding to and blocking the Wnt co-receptor LRP5/6. Its function in blocking osteoblastogenesis makes it an important target for osteoanabolic therapy approaches to treat osteoporosis, which is characterized by a progressive decrease in bone mass and density. In this work, the production, crystallization and preliminary X-ray diffraction data analysis of a sclerostin-neutralizing human Fab antibody fragment, AbD09097, obtained from a naive antibody library are reported. Crystals of the Fab AbD09097 belonged to space groupP21, with unit-cell parametersa= 45.19,b= 78.49,c= 59.20 Å, β = 95.71° and diffracted X-rays to a resolution of 1.8 Å.