Bone Abstracts

Osteoclast-poor autosomal recessive osteopetrosis is characterised by susceptibility to fracture despite high bone mineral density as a consequence of an absence of osteoclasts. One of the 12 receptor activator of NF-κB (RANK) mutations associated with this condition is a frameshift mutation encoding a protein that is truncated within the extracellular, N-terminal domain (R110Pfs). We investigated the effect of this mutation on osteoclast formation, receptor localisation ...

Objectives: The Brtl mouse, a unique model for the autosomal dominant forms of osteogenesis imperfecta was used to prove the feasibility of a lentiviral-shRNA-based strategy to improve collagen quality by targeting the mutant Col1a1 allele at the point mutation responsible for the causative substitution Gly349Cys. The ability to specifically suppress the mutant allele should convert the moderate Brtl outcome to the mild one caused by quantitative defect.<p class="...

Background: High doses of zoledronic acid (ZOL), one of the most potent inhibitors of bone resorption; is currently evaluated in a phase III clinical trial in Europe for the treatment of malignant pediatric primary bone tumors. The impact of such an intensive treatment on the craniofacial skeleton is a critical question in the context of patients with actively growing skeleton; in particular in the light of our previous studies evidencing that endochondral bone formation was t...

Objectives: Childhood osteoporosis can be treated with i.v. bisphosphonates in order to improve bone mass and density. The aims of this study were to evaluate the safety and efficacy of 6-monthly zoledronic acid (ZA) in children with osteoporosis.Methods: A retrospective cohort study of 27 patients (16 males and 11 females) were treated with 6-monthly ZA (0.05 mg/kg per dose) for a minimum of 1 year. Seventeen patients were immobile, 4 had steroid-induce...

Shwachman Diamond syndrome (SDS; MIM 260400) is a monogenic, autosomal recessive, pancreatic condition often accompanied by low bone mass and fracture. In SDS, as in cystic fibrosis, a low bone mass may be secondary to poor nutrition or chronic low-grade infection, but it has also been suggested there may be a primary bone phenotype. Paradoxically, recent studies in cell lines and in a mouse knockout for the SBDS gene, have suggested changes in important osteoclast gr...

Twelve different mutations in TNFRSF11A (encoding the RANK receptor) have been associated with osteoclast-poor autosomal recessive osteopetrosis in patients. Two truncated RANK proteins resulting from substitution mutations (W434X and G280X), identified in two infants, cause loss of the intracellular oligomerisation motif and in the case of the G280X mutation the TRAF6 binding domain. A third mutation was identified in a 10-year-old patient and is a frameshift mutatio...

Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis (survival rate drops to 20% when lung metastases were detected). Because TGF-β has been shown to promote metastases in many solid tumors, we investigated the effects of inhibition of the TGF-β/Smad cascade on osteosarcoma behavior. To this end, two independent procedures, a pharmacological approach ...

Objective: There is no published data to demonstrate the efficacy and safety of a single bolus dose vitamin D in breastfed infants of vitamin D deficient mothers. We evaluated the efficacy and safety of this alternative approach in newborn infants <4 months of age.Method: This single centre study was conducted from Aug 2013 to May 2014. Of 307 pregnant women diagnosed with vitamin D deficiency (25OHD<50 nmol/l) 70 were recruited. Their newborn in...

While the importance of interactions between bone and tumors is well-established, the mechanism by which the physical bone microenvironment regulates disease progression is limited by the lack of suitable in vitro models. We have designed 3D Tissue Engineered Constructs (TECs) using microCT imaging in tandem with inkjet 3D printing technology that recapitulate the mechanical and morphometric properties of trabecular bone. 3D-printed TECs exhibited no significant diffe...

It is well established that tumor expression of Gli2, a Hedgehog family transcription factor, contributes to tumor-induced bone disease. Our previous studies investigating genetic inhibition of Gli2 expression in tumor cells have shown promise for the development of therapeutics. While many groups have focused on developing upstream Hedgehog inhibitors for soft-tissue tumors that aberrantly express Gli proteins, we have previously demonstrated that the expression of Gli2 in tu...