Bone Abstracts

It has been established that disturbances of intracellular signaling pathways strongly contribute to the oncologic process. Indeed, phosphatidylinositol-3-kinase (PI3K) became a key target in cancer therapy, due to its high frequency of mutation and/or gain of function of its catalytic subunits in cancer cells. In this context, we investigated the in vitro and in vivo effects of a new PI3Kα inhibitor, BYL719 (Novartis Pharma), on bone cells and its thera...

Osteosarcoma is the most common primary malignant bone tumor, characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments points out the importance of exploring new therapeutic ways. Imatinib Mesylate (Glivec, Novartis Pharma), a tyrosine kinase inhibitor, has been originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that Imatinib Mesylate inhibits osteoclast differentiation th...

Osteoclast (OC)-mediated bone destruction is a key feature of rheumatoid arthritis (RA). In RA synovial tissue a reduced density of catecholaminergic nerve fibres has been observed. Studies on sweat gland innervation proved that catecholaminergic fibres have the ability to undergo a phenotypic transition to cholinergic nerves. The sympathetic neurotransmitters norepinephrine (NE), acetylcholine (ACh), and vasoactive intestinal peptide (VIP) affect osteoclastogenesis oppositely...

Objective: Chondrolysis, chondrocyte apoptosis, and local inflammation are described to exacerbate osteoarthritis development. We therefore aimed to investigate the effect of adrenomedullin (ADM) and its truncated peptide (22–52ADM) on in vitro and in vivo models. Both have exhibited anti-apoptotic and anti-inflammatory properties in collagen-induced arthritis (CIA) in mice.Methods: In normoxia or hypoxia (physiological condition),...

Sclerostin, a product of osteocytes, is known to inhibit Wnt signaling by binding the LRP5/6 receptor.We investigated the effects of a mutated mouse sclerostin protein (muScl, R118A/R144A) with potential sclerostin antagonistic activity. In vitro, muScl fully competed with wild type sclerostin for binding to LRP6, whereas its IC50 for Wnt3a activity was 4× higher than sclerostin (i.e. 600 nM). Moreover, serum osteocalcin increased in mice a...

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...

Purpose: Sclerostin, a Wnt inhibitor produced by osteocytes that regulate bone remodelling, might be involved in cartilage metabolism. Therefore, we assessed the effect of sclerostin in osteoarthritis using SOST-deficient mice.Methods: SOST-KO and wild type (WT) mice underwent partial meniscectomie (Mnx). Mice were sacrificed at 4, 6 or 9 weeks after Mnx to analyze i) bone volume (BV/TV) at the femoral condyle, ii) osteophyte volume (microCT), iii) carti...

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 ...

Interleukin-34 (IL-34) is a newly discovered cytokine which regulates, like macrophage-colony stimulating factor (M-CSF), the differentiation/activation of the myeloid lineage. IL-34 and M-CSF are homodimers known to bind to the M-CSF receptor (M-CSFR) in a competitive manner. In this system, IL-34 can substitute for the M-CSF to induce osteoclastic differentiation. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the...