A Disintegrin And Metalloproteinase 12 produced by tumour cells accelerates osteosarcoma tumour progression and associated osteolysis.

Background: Osteosarcoma is the most common primary malignant bone tumour in children and adolescents for whom the prognosis remains unfavourable despite treatment protocols that combine chemotherapy and surgery. Metalloproteinases decisively contribute to cancer development and promotion by regulating cell growth, angiogenesis or inflammation. However, their role in osteosarcoma remains still unknown.

Proteoglycans and osteolysis.

Osteolysis is a complex mechanism resulting from an exacerbated activity of osteoclasts associated or not with a dysregulation of osteoblast metabolism leading to bone loss. This bone defect is not compensated by bone apposition or by apposition of bone matrix with poor mechanical quality. Osteolytic process is regulated by mechanical constraints, by polypeptides including cytokines and hormones, and by extracellular matrix components such as proteoglycans (PGs) and glycosaminoglycans (GAGs).

Modulatory effects of proteoglycans on proteinase activities.

Proteoglycans (PGs), composed of a core protein and one or more covalently attached sulfated glycosaminoglycan (GAG) chains, interact with a wide range of bioactive molecules, such as growth factors and chemokines, to regulate cell behaviors in normal and pathological processes. Additionally, PGs, through their compositional diversity, play a broad variety of roles as modulators of proteinase activities. Interactions of proteinases with other molecules on the plasma membrane anchor and activate them at a specific location on the cell surface.

Influence of Tumor Necrosis Factor α, Parathyroid Hormone, and Vitamin D3 on Modulation of the RANKL2 Isoform: A Pilot Study.

RANKL exists as three isoforms: RANKL1, 2, and 3. RANKL1 and 3 were reported to be differently expressed upon treatment with some osteotropic factors, but RANKL2 expression could not be reliably determined. Here, we investigated through a mechanistic model, human 293 cells stably transfected with the RANKL2cDNA, the production and modulation of RANKL2 protein stability upon treatment with TNF-α, vitamin D3, and PTH.

Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: role in osteoclastogenesis and bone resorption.

The bone microenvironment (e.g. glycosaminoglycans (GAGs), growth factors) plays a major role in bone resorption, especially in the formation of osteoclasts which differentiate from the hematopoietic lineage in the presence of RANKL.

Proteoglycans on bone tumor development.

Proteoglycans, extracellular matrix components, exert several activities on bone cells and seem crucial for maintaining an appropriate number of osteoblasts and osteoclasts. The overall data strengthen a pro-bone resorptive role for proteoglycans, through the control of osteoprotegerin availability and of receptor activator of NF-kappaB ligand bioactivity. In parallel, proteoglycans participate in the control of tumor development at different levels, including bone tumor development and bone metastases dissemination.

New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target?

Bone remodelling is tightly regulated by a molecular triad composed of OPG/RANK/RANKL. The receptor activator of NF-kappaB ligand (RANKL) (localized on osteoblasts) enhances osteoclastogenesis via interaction with its receptor RANK (localized on osteoclasts), whereas osteoprotegerin (OPG) (produced by osteoblasts) inhibits this osteoclastogenesis by binding to RANKL. The equilibrium between OPG and RANKL plays a crucial role in the pathophysiology of bone.

OPG/membranous--RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteasomal degradation.

The members of the OPG/RANK/RANKL (osteoprotegerin/receptor activator of nuclear factor kappaB/RANK ligand) triad are involved in various osteolytic pathologies such as bone tumors. Although many studies described the use of OPG during the treatment of bone diseases, its bioavailability and the mechanism by which the cells control the extracellular OPG remains blurred. The present work uses a strongly RANKL expressing cellular model to assess the becoming and the bioavailability of exogenous OPG in the context of its interactions with RANKL.

Osteolytic bone diseases: physiological analogues of bone resorption effectors as alternative therapeutic tools.

The recent identification of key molecular protagonists involved in osteoclast biology has led to the development of new therapeutic approaches of osteolytic diseases using biological molecules which could compete with bisphosphonate therapy.

IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology.

All osteogenic cells (osteoclasts, osteoblasts) contribute individually to bone remodeling. Their cellular interactions control their cellular activities and the bone remodeling intensity. These interactions can be established either through a cell-cell contact, involving molecules of the integrin family, or by the release of many polypeptidic factors and/or their soluble receptor chains.