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Molecular interactions hold the key to relieving bone loss

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Major crippling diseases worldwide may be amenable to treatment with inhibitors of a system that controls bone loss, according to a review of the molecular events in bone metabolism and arthritis.

The balance between bone loss by osteoclasts and bone formation by osteoblasts in normal bone metabolism is controlled by molecules in the TNF-TNFR superfamily.

RANKL (ligand to receptor activator of NFκB) is a membrane bound protein of osteoblasts and is produced also by activated T cells. Its receptor, RANK, is a transmembrane protein in osteoclasts and chondrocytes. OPG (osteoprotegerin) is a soluble competitive decoy receptor for RANKL binding. The degree of the RANKL-RANK interaction determines bone loss.

Importantly, this system operates in all animal models of arthritis so far studied, causing bone loss and eventual crippling, both of which OPG prevents. The hope is therefore that OPG can be used in various forms of arthritis in humans and in some immune disease—leukaemia, cancer metastasis, and autoimmune diseases.

Results so far are promising. OPG prevents bone destruction in cancer and metastatic associated bone pain, when bone destruction is associated with T cell activation. Further understanding of the pathogenic process and how T cell dependent RANKL is regulated may hold the possibility of cytokine inhibitors for clinical use.

Many conditions apart from arthritis and osteopenic disorders cause bone mineral density to fall. The burden of arthritis alone is enormous: one person in a hundred will have rheumatoid arthritis in Europe and North America and one in ten osteoarthritis.

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