Mechanosensitivity of osteoporotic stem cells for diagnosis and treatment of osteoporosis

Osteoporosis is the most common bone disease in humans, affecting over a quarter of people aged 50+ years. The condition predominantly affects post-menopausal women and results in over 500,000 fragility related fractures p/a within the UK. The elevated fracture risk from everyday activities, due to weakened bones, is a major challenge for our aging population. Current pharmaceutical treatment options, such as bisphosphonates, are proving insufficient to provide long term fracture protection. To ensure bone health into older age, new treatment modalities are required, representing an opportunity for bioengineering strategies.
Mechanical loading is a key factor in maintaining bone health. Homeostasis of bone density is a result of balance in the activities of osteoblasts and osteoclasts, which are both mechanically sensitive. A lack of loading (e.g. during zero-g spaceflight or extended bed rest) has been show to result in increased bone resorption and a loss of bone density. In age-related osteoporosis, the disease is not necessarily due to a lack of loading per se, but can be a failure of bone cells to respond sufficiently to mechanical signals. Therefore, one resulting hypothesis is that osteoporosis directly results from altered mechanotransductive signalling mechanisms at the cellular level.
Prior research has focussed on methods of mechanically stimulating cells in vitro, such as the use of nanoamplitude vibration. The use of certain vibration parameters (1 kHz, 30 nm amplitude) has shown effective osteogenic stimulation of adult mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue. This stimulation method includes activation of mechanotransductive pathways via ROCK signalling and mechanosensitive ion channels with a potential dependence on vibration amplitude. The process alters focal adhesion conformation and increases cellular tension through increased actin-myosin contractility, potentially also changing cellular mechanical properties as measured by in vitro techniques (e.g. AFM, cell deformation). In the case of MSCs, this leads to differentiation towards a high contractility osteoblastic phenotype and increased mineralisation, without recourse to osteogenic reagents or growth factors. However, the differences in mechanotransductive response between healthy and aged/osteoporotic MSCs are yet to be studied.
Alongside in vitro cell stimulation studies, development of wearable devices which can apply nanovibration directly to patients has begun. Before this technology can be applied to the clinical challenge of osteoporosis, there needs to be further understanding of the mechanotransductive response of osteoporotic bone cells compared to healthy osteogenic cells residing within the bone marrow cavity. In addition, the identification of suitable administration options for a vibrational therapy (in terms of duration, amplitude and frequency) may need to be reconsidered for bone cells in the diseased state.
RESEARCH OBJECTIVES
1. To study phenotypic changes of osteoporotic stem cells under various levels of mechanical loading across different age groups.
2. To determine if cellular mechanical properties (e.g. stiffness, deformability) could be used as a diagnostic of bone forming capacity and onset of osteoporosis or reduced mechanotransductive signalling.
3. Use in vitro data to develop therapeutic nanovibration protocols which could be applied practically via wearable vibration devices