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Our research focuses on identifying targets for the development of drugs to prevent bone destruction in rheumatoid arthritis through understanding how hypoxia affects bone removal by osteoclasts.

Hypoxic osteoclasts resorbing bone in rheumatoid arthritis express both HIF-1α and ANGPTL4
Hypoxic osteoclasts resorbing bone in rheumatoid arthritis express both HIF-1α and ANGPTL4

Osteoclasts are cells that specialise in removing bone. In rheumatoid arthritis (RA) the normal regulatory processes have been disrupted and osteoclasts are both more numerous and more active. Because of the tissue damage that is also present in RA the blood vessels are disturbed, which interrupts the supply of nutrients to the joint. A side-effect of this is lack of oxygen, known as hypoxia.

We have discovered that hypoxia increases the amount of bone removal by osteoclasts and that this increase in activity is regulated by a protein called HIF (Hypoxia-Inducible Factor).

We are now trying to identify the mechanism(s) whereby HIF controls this process, with the long-term goal of identifying target(s) for the development of drugs to inhibit osteoclast activity and prevent bone destruction in RA.

We currently have 3 main projects:

1. Investigating the effects of HIF over-expression on bone in vivo

HIF is regulated by the HIF prolyl hydroxylase (PHD1-3) enzymes. We are using PHD1, PHD2 and PHD3 knock-out mice to identify effects of PHD inhibition on bone phenotype in vivo, as well as on the formation and activity of osteoclasts (bone resorption) and osteoblasts (mineralisation) ex vivo.

2. Angiopoietin-like 4 (ANGPTL4) and bone resorption

We found that the adipokine ANGPTL4 specifically stimulates the bone resorption activity of osteoclasts. We are now following up preliminary data that high serum levels of ANGPTL4 in RA patients correlate with markers of bone loss in this disease.

3. Hypoxic metabolism of osteoclasts

Bone resorption is very energy-intensive. We discovered that hypoxic osteoclasts generate sufficient energy for this process by increasing flux though both the glycolytic pathway and mitochondrial electron transport chain. This quickly produces toxic amounts of reactive oxygen species (ROS) leading to cell death, perhaps a self-limiting mechanism to prevent excessive bone loss. We are now investigating whether we can modulate the balance between hypoxia-induced osteoclast activation and hypoxia-induced osteoclast apoptosis to slow or inhibit pathological bone destruction.

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