Our lab is defining the actions of bisphosphonate drugs – a ‘blockbuster’ class of agents used to inhibit bone destruction in patients with common bone disease, such as post-menopausal osteoporosis and cancer-associated bone loss.
Our past research discovered that these drugs work by blocking an enzyme of the mevalonate (cholesterol biosynthesis) pathway, which is essential for the function of osteoclasts – cells that break down bone tissue.
Building on this knowledge, our current research seeks to understand how bisphosphonates appear to have other beneficial effects outside the skeleton, such as reducing the risk of pneumonia infection and preventing tumour growth. Using a variety of approaches, including direct imaging of cells in the body, our findings have revealed that bisphosphonates can inhibit the mevalonate pathway in certain immune cells (macrophages) in the lung and in tumours, debunking the long-held view that these drugs act only on bone cells.
By developing new laboratory models, we are also studying how bisphosphonates have side-effects through the activation of bystander cells such as gamma-delta T cells. Understanding the exact mechanisms involved will allow us to develop ways of preventing unwanted side-effects while maintaining all of the beneficial effects of these drugs.
The mevalonate pathway and inflammatory disease
Our expertise in the mevalonate biosynthesis pathway has led to a new research focus on mevalonate kinase deficiency (MKD, also known as HIDS) a rare autoinflammatory disease caused by mutations in an enzyme in this pathway. We have demonstrated that protein prenylation, which is dependent on the mevalonate pathway, is defective in circulating blood cells in patients with this disorder. This approach may be used as a biomarker to help diagnose MKD and distinguish it from other autoinflammatory disorders with similar symptoms. More recently, we have developed new laboratory models of MKD that are providing exciting new insights into the mechanisms of disease and offer new opportunities to test novel therapeutic approaches to restore the mevalonate pathway and prevent inflammation.
- 2022The Journal of clinical investigation10.1172/JCI160929
Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency.
Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.
- 2019Frontiers in immunology10.3389/fimmu.2019.01900
Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency.
- 2019The Journal of allergy and clinical immunology10.1016/j.jaci.2019.02.013
Lack of protein prenylation promotes NLRP3 inflammasome assembly in human monocytes.
- 2017The Journal of allergy and clinical immunology10.1016/j.jaci.2017.02.033
Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency.