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91ֱ�� the biobank

The aim of the biobank is to make use of these clinical and tissue resources to address research questions relevant to musculoskeletal disease. The biobank holds tissue samples obtained from donors and completed, ethically approved projects with appropriate consent for biobank storage and use for future research projects. 

Samples are stored in the 91ֱ�� Biorepository, which is an HTA-licensed facility.  The biobank operates under the guidance of a steering committee to assure compliance with current best ethical practices. 

All applications for use of tissue through the SYNDMB are submitted in collaboration with a member of the Academic Unit of Bone Metabolism and reviewed by the SYNDMB Steering Committee, which includes representatives from the Biorepository, STH Research Office, Lay members of the public and clinicians from the Metabolic Bone Centre and Orthopaedics.

Recent project applications

Is calcium isotope ratio a useful tool to assess bone health?

There are several forms of calcium molecules in the environment. These calcium isotopes have the same atomic number but different atomic masses. Calcium-40 is the most abundant form of calcium, but calcium isotopes, such as calcium-42 and calcium-44, occur naturally in the environment.

Because some isotopes are heavier than others, they are handled differently by the skeleton, making the calcium isotope ratio a potential tool to assess bone. Similarly to bone turnover markers, which provide an estimate of bone renewal, we hypothesise that, by looking at the ratio of calcium isotopes, we can get a glimpse into the overall health of our bones. If our bones are strong and healthy, the ratio will reflect that.

Some initial results suggest that this tool has the potential to help doctors and scientists better understand bone diseases and how to keep our bones strong, but more research is needed to investigate this.

Therefore, we want to assess calcium isotope in different settings: in postmenopausal women with and without vertebral fractures, in the same set of patients, in several timeframes, in healthy premenopausal women, and in women in use of osteoporosis treatments. We will investigate if calcium isotopes can help us understand and improve bone health.

Osteoarthritis ex vivo culture model to understand pathogenesis and develop and test new therapeutic strategies

Osteoarthritis is a major cause of disability worldwide, leading to substantial pain, and decreased mobility, with major impacts on individuals' quality of life. However, despite the debilitating effects, current treatments are inadequate. Many individuals are faced with poor treatment options which only tackle symptoms of the disease, which in many cases fail, with patients prescribed multiple painkillers and are hampered by severe side effects. Thus, there is an urgent need to develop a better understanding of the causes of osteoarthritis and develop treatments that tackle the disease rather than just symptoms. 

Osteoarthritis is the result of abnormal cell behaviour and mechanical damage. Resulting in increased production of natural chemicals, which damage the joint tissues and stimulate local nerves, leading to pain. Within this study, we aim to develop a laboratory culture system where we can maintain living human knee or hip samples from the waste tissues normally discarded during knee and hip replacement surgery. We will combine cores of tissue consisting of cartilage and underlying bone with tissue pieces removed from the joint lining.

These cultures will enable the cell-to-cell cross-talk which occurs in the body to take place in the lab. These culture systems will be used to gain an improved understanding of the development of the disease as we can culture separate regions of tissue representative of ‘non-diseased’ and ‘diseased’ regions to understand differential cell and tissue behaviour. 

These cultures will enable the testing of a wide range of potential treatments including drugs and gene therapy approaches to replace missing proteins, and cell and biomaterial strategies to induce regeneration of the tissue. The utilisation of human tissue samples from osteoarthritic patients will accelerate clinical translation ensuring any identified targets will be successful in the final target population.

SYNDMB68: Preclinical development of STING-TMEM203 inhibitors to treat Systemic Lupus Erythematosus

Lupus is a lifelong autoimmune condition affecting 1 in 1000 people where over-active inflammation causes severe tiredness, joint pain, and risk of damage to organs including the heart and kidneys.

Lupus disease flares are treated with medicines that stop the inflammation but come with side effects that increase the risk of becoming very ill from infections and cause muscle weakness and brittle bones. The recent approval of a new antibody treatment for lupus is safer but a much more expensive class of drug, making it impractical for widespread global healthcare. 

We have recently identified simple chemical compounds that may do the same job as the expensive treatment. We predict these chemical compounds will be as effective as the new expensive treatment but without the risk of knocking out the immune system and would be much less expensive to produce for global healthcare. 

In this project, we aim to isolate immune cells from the blood of consented lupus patients and test if our chemical compounds can reduce inflammation in their blood-derived immune cells. We will collect clinical information, to determine if patients were experiencing inflammatory flares at the time of blood donation.

This testing will provide preliminary information on how effective our chemical compounds are in reducing inflammatory flares in lupus cells. This evidence will make a good case for a much larger scale study exploring the safety, and drug properties of the chemical compounds, for development into clinical trials.

Validating microRNA biomarkers to optimise prediction and treatment of ageing and osteoarthritis, osteoporosis

Our research focuses on the effects of ageing on our musculoskeletal tissues (bone, muscle, cartilage and tendon) and vice versa (for example, do diseases of our musculoskeletal tissues, such as osteoarthritis, influence the rate at which we age?)  The role of our genes in ageing and musculoskeletal disease is of increasing interest and recently has involved new knowledge about how our genes’ abilities to produce specific proteins are switched on and off.

One of the ways in which genes are ‘switched off’ is by inhibition of the message, carried by a molecule called ribonucleic acid (RNA), from the gene to the part of the cell that produces the particular protein.  This inhibition is carried out by small RNA molecules (called microRNAs; miRNA) which bind to the RNA and stop the protein from being produced, potentially contributing to the development of disease.  Many miRNAs can be detected in blood samples and measurement of these might be useful in predicting or understanding diseases; if useful, such factors are called biomarkers. 

This application for samples will allow us to study these promising biomarkers by looking at their levels in subsets of older women from within the MRC Hip study.  This study, started in 1996, followed over 5200 women aged 75 and older in 91ֱ�� for up to 5 years, during which some women sustained a broken hip (hip fracture) while most remained free of hip fracture. Likewise, some women died during follow-up whereas other lived longer than the duration of the study.

In these serum samples, we will examine whether microRNAs can detect women at increased risk of either of these outcomes (hip fracture or death). Such information could, for example, lead to the potential use of miRNA to improve the targeting of treatment to those older women at the highest risk of hip fracture.

sRNA Transcriptome Analysis to Identify Differentially Expressed miRNA in Blood Serum Between Individuals with Osteolysis and Healthy Controls: An exploratory analysis

Osteolysis of the hip is a condition where the bone around a joint replacement implant breaks down causing the replacement to become loose and causing pain. The only treatment for this problem is to take out the loose implant and replace it with another one. This is a highly undesirable outcome as it is associated with more pain, poorer walking ability and higher cost than the initial total hip replacement.

Small but powerful chemicals exist within our cells known as micro-RNAs that can change the way in which our cells behave. The levels of different micro-RNAs have been shown to be different between healthy individuals and those with a disease. Some basic research has already been performed on specific micro-RNAs in osteolysis. However, we can now test for all micro-RNAs using a single test. This may allow us to identify a broad, previously unseen range of micro-RNA differences between individuals with and without osteolysis.

The results of this research could give us a better idea of how to look for better diagnosis and treatment methods for osteolysis in the future

Evaluation of the Xtreme CT device for the assessment of bone: Further biochemical assessment 2

We want to better understand how people get weaker bones as they get older. We suspect that it could be caused by chemicals in the blood that controls the way bone is constantly broken down and replaced.

The plan of this study is to measure these chemicals in the blood of healthy men and women between the ages of 16 and 75 and test whether their levels might explain the levels of chemicals that reflect the changes in the bone as we get older. We are making use of blood samples that are stored in the Biobank. We have already a lot of information on these subjects.

Identification of control group for evaluation of miRNAs and bone quality in type 2 diabetes

Type 2 diabetes is a disorder in which the insulin produced by the pancreas does not function properly or the pancreas is not able to produce enough insulin. As a result, the amount of glucose (also known as sugar) in the blood remains high. Due to type 2 diabetes, bones in these patients become weak and are prone to fractures. The reasons why this happens are not well understood. We believe that understanding bone quality may be helpful to understand why patients with type 2 diabetes are more prone to fractures, also known as diabetic bone disease.

In our blood, there are several factors or molecules that help in normal body functioning. These factors are also important for good bone health. The levels of these factors or molecules are different between healthy people and those with disorders. Hence, we aim to develop suitable biomarkers from these factors or molecules for diabetic bone disease. 

Our project collaborator, Dr Morten Frost (Southern Denmark University, Odense, Denmark) has recruited 200 patients with type 2 diabetes. Blood samples as well as bone scans from these patients are available. Unfortunately, no healthy control population is available. Hence, we aim to identify healthy controls from the following studies based here in 91ֱ��: STH14463, SHT16353 and STH15688 (details below).

We plan to work with experienced teams to measure these factors or molecules in patients with type 2 diabetes and healthy controls. We will also look for associations between these factors or molecules and measurements from bone scans using appropriate tools. This large number of measurements will help us develop these factors or molecules as biomarkers to better understand disorders related to bone quality in patients with type 2 diabetes.

Are differentially expressed proteins identified at joint cartilage level that associate with osteoarthritis detectable in serum? A discovery analysis

Osteoarthritis is one of the most common chronic long-term conditions of the modern age and affects an estimated 1 in 20 of the world’s population. Osteoarthritis is currently a disease without any cure. We treat the patient with advice and painkillers until the disease gets to a stage where surgery can be used to remove and replace the damaged joint.

While we are working towards new treatments that may one day avoid the need for surgery, we also need to advance our knowledge of how the disease develops and how we might detect the disease earlier in its course. By identifying the disease in its early stages, we may be able to develop treatments that could slow its progression.

The purpose of the study proposed here is to see whether some of the chemicals we find in the joints of patients who have arthritis might also be found in their blood. This is an exploratory study (a first look to see if this is possible) and would not lead directly to a new blood test for arthritis, but rather guide us in the right direction.

We plan to compare blood samples from ~300 patients with known osteoarthritis of the knee with ~300 from patients of broadly similar age and sex from the background population to see if blood protein profiles indicate an osteoarthritis “signature”. If we find such a difference, we would plan to re-run the analysis in further independent patient populations.   

Are advanced glycation end products (AGEs) biomarkers of long-term low bone remodelling?

Most of the risk of fractures is estimated by bone density but other features like bone quality also play a role. Sugars can spontaneously link to proteins and form advanced glycation end products (AGEs). Therefore, AGEs are harmful compounds that are formed when protein or fat combine with sugar. This reaction leads to the browning of proteins and can modify their properties. The collagen in the ageing skeleton is affected by the formation of AGEs, making the bones brittle. 

We believe that AGEs can give us information on bone quality; how bone is renewing itself. Low renewal would allow more sugars to bind to collagen and increase AGEs. Some conditions are associated with increased AGEs and also increased risk of fractures. For example, diabetes is associated with higher sugars, higher AGEs and higher risk of both atypical femur fractures and osteoporotic fractures

We want to investigate if AGEs can give us information about bone quality and long-term bone renewal. We will measure AGEs in people who received bone-building treatment and antiresorptives. We suspect that bone-building treatment will reduce AGEs while antiresorptives will increase them. This might help us to personalise the therapy in the future; identifying people with poor bone quality and chronic low bone renewal at higher risk of atypical femur fractures.

Preclinical development of mesenchymal stem cell-based regenerative therapy for the treatment of human Osteoarthritis

Osteoarthritis is one of the most common causes of chronic disability in the UK and worldwide, affecting approximately 13% of the population. The key problem with arthritis is damage to the cartilage that covers the joint and makes it work smoothly. Unfortunately, although we can do a joint replacement to treat the symptoms of arthritis, to date we have no cure for the cartilage disease itself. The overall aim of the research proposed here is to explore whether we can help arthritic joints to “heal” by using cartilage cell injections to help the patients' own cartilage to regenerate.

What we are proposing here is very early-stage experiments to see if we can take fat cells from donor patients undergoing joint replacements and reprogramme them to turn into cartilage cells. We will then grow the cells in the lab to see if we can make them behave like cartilage cells and also test whether they would be safe to transplant into other patients in future studies. This early stage “in-vitro” or lab work, has been funded by the Medical Research Council, who are interested to help us see if this might in future be an alternative treatment to joint replacement for the 9 million people in the UK who suffer from arthritis.