Drug Discovery Opinion

Many reports have linked high cholesterol with osteoporosis and HMG-CoA reductase inhibitors (statins) have been proposed to reduce the risk of fractures, although clinical data have been more equivocal than results from animal studies. Mechanisms for the beneficial actions of statins on bone density have been proposed, but a new study by researchers at UCLA has focused on the link between bone loss and the immune system. Recent evidence has pointed to a role for RANKL (Receptor Activator for Nuclear Factor κB Ligand) in bone metabolism by activating osteoclasts and increasing bone resorption. RANKL is produced by activated T-cells and is involved in mediating interactions with dendritic cells. Since products of lipid oxidation are known to affect T-cell function and to contribute to inflammation and metabolic disorders, the UCLA team hypothesised that production of RANKL might be modulated by oxidised lipids. Both unstimulated and activated human T-cells significantly increased production of RANKL and expression of the lectin-like oxidized LDL receptor-1 (LOX-1) on short term exposure to minimally oxidised LDL but not on exposure to native LDL. The effect was shown to be mediated by via the NFκB pathway and involve increased RANKL mRNA expression.

In follow-up studies in hyperlipidaemic mice, bone loss was found to be associated with increased RANKL mRNA in T lymphocytes as well as elevated RANKL serum levels. The finding that oxidised lipids contribute to bone changes by increasing RANKL production by T-cells may explain the link between cardiovascular disease and osteoporosis and also suggests the possibility of new immune-based therapies for osteoporosis.

The study was published on August 20^th in the journal Clinical Immunology.

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