07. Musculoskeletal - Recent Highlights

An aim of the musculoskeletal component of the BRC has been the collection of data on cytokine production and alternations in T lymphocyte subsets in patients with inflammatory arthritis. There has been considerable interest in newly identified T cell subsets in the last 5-10 years, particularly T cells with regulatory capacities and those which make the cytokine IL-17, which has been implicated in a number of animal models of inflammatory arthritis. In patients with ankylosing spondylitis we have characterised an expanded population of CD8+ T cells with potent regulatory functions, and we are investigating the pathogenetic role of this subset. It may represent an inflammation-induced negative feedback mechanism; whilst this is clearly not effective since patients continue to have active inflammation, it is a mechanism that might be exploited therapeutically.

We were the first laboratory to document increased numbers of T cells making IL-17 in peripheral blood of patients with ankylosing spondylitis and in the related condition of reactive arthritis. The phenotype of these cells, and the other cytokines they produce, has been investigated together with their presence at the site of inflammation. These findings have led to additional studies on factors driving the differentiation and expansion of IL-17 producing T cells. These observations are timely in view of the availability of therapeutic antibodies to both IL-17 and the principal IL-17-driving cytokine, IL-23, and rational use of these therapies will be guided by the observations we have made.

These studies were greatly facilitated by the BRC, which enables us to obtain blood and synovial fluid samples from well characterized patients in routine clinics and to perform phenotyping studies of the kind outlined above. This approach will be continued and extended to other components of the BRC through the opening of the immunophenotyping hub in 2011.

With worldwide annual hip fracture rates predicted to exceed six million by 2050, the need to identify and intervene effectively in those at risk of hip fracture is of profound scientific, social and economic importance. The distribution of cortical bone in the proximal femur is believed to be the key determinant of fracture resistance and we have made rapid advances in the development of a novel imaging biomarker of hip fragility that has the potential to revolutionise hip fracture prediction and has already identified for the first time the precisely targeted response of osteoporotic hips to bone-building treatments.

The 2009 patented technique effectively de-blurs in-vivo CT data from clinical scans, enabling assessment of regional thinning by means of a colour map of cortical thickness. Our recent studies have shown that the effects on cortical bone of the bone building drug teriparatide (parathyroid hormone peptide 1-34) are targeted to sites of mechanical loading. The practical healthcare implication of this finding is that bone-active drugs may need to be administered alongside targeted exercise to maximise bone strength.

Another new approach to non-invasive in vivo bone imaging is the MR-based technique of structural spectroscopy, which enables site-specific assessment of cortical and trabecular bone microarchitecture in the axial and appendicular skeleton. We are currently conducting a study with Osteotronix, who have developed this technology, to determine the ability of this technique to predict bone fragility and fracture risk in patients with low bone mineral density. In collaboration with a group at Guys and St Thomas' Hospital, London, we are also investigating the utility of fluoride-labeled PET-scanning to measure regional bone blood flow and bone turnover, using comparison with directly assessed indices of bone turnover in iliac crest biopsies.

Analysis of the database from our Fracture Liaison Service, which is funded by the BRC, resulted in the new observation that fractures in obese postmenopausal women make a major contribution to the global fracture burden in this population. Collaborations have been forged with large international population-based prospective studies to pursue further these findings and to establish the pathogenesis of fractures associated with obesity. Important findings to date have been that obesity is a risk factor for certain fracture types, particularly fractures of the ankle and lower leg, and that poor physical function and increased risk of falling are important determinants of fracture risk in these women.