Skeletal ageing is governed by bone cell metabolism. Common factors may exist linking cellular energy metabolism with lifespan and skeletal heath, such as those targeted by anti-diabetic drugs metformin and fenofibrate. We have used cellular and molecular studies, in combination with genetically modified mouse models to investigate the effect and mechanism of such systems on the skeleton. Pre-osteoblasts (2T3) were differentiated in vitro for 12 days in osteogenic media, in the presence of fenofibrate (5-25 μM), metformin (5-500 μM) or a small molecule activator of the adiponectin receptors (AdipoRON, 5-25 μM). Metformin significantly reduced metabolic activity and cell viability (MTS & alamar blue assays) of differentiated 2T3 cells. 2T3 mineralisation (Alizarin Red staining) was not affected by metformin, yet mineralised particle number and total mineralisation area were significantly increased by AdipoRON (4.6 and 6.0-fold, respectively, p<0.01) and fenofibrate treatments (8.9 and 10.0-fold respectively, p<0.001) relative to vehicle controls. Fenofibrate and adiponectin signalling directly activate the nuclear ligand receptor PPARα, which regulates fatty acid catabolism and transport, and interacts with known ageing-related pathways. We hypothesised that PPARα may act as a master regulator of the skeleton and mediate age-related changes in bone in vivo. This was tested by analysing the skeletal phenotype of middle (~7 months) and old-aged (~15 months) PPARα-/- or wildtype control mice using micro-CT and histomorphometric analysis. Cortical density was significantly decreased in PPARα-/- relative to control mice at both ages (p<0.001), with specific low density areas of cortical bone identified with large cartilaginous remnants. PPARα-/- trabecular BV/TV was not different to controls at middle age. However, unlike the BV/TV of wildtype mice, PPARα-/- BV/TV did not decrease with further ageing. Adiponectin signalling may have a beneficial effect on bone formation through PPARα, raising a putative novel use for the fibrate class of PPARα-activators for improving bone quality with ageing.
Disclosure: The authors declared no competing interests. This work was supported by Arthritis Research UK.