PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) was first identified in 2015 by University of Birmingham researchers. PEPITEM is a naturally occurring short protein (peptide) produced in the body and found circulating in everyone at low levels.
The latest research, published today in Cell Reports Medicine, show for the first time that PEPITEM could be used as a novel and early clinical intervention to reverse the impact of age-related musculoskeletal diseases.
Bone is constantly formed, reformed, and remodelled throughout life, and up to 10% of human bone is replaced annually through a complex interplay between two cell types – osteoblasts, which form bone, and osteoclasts, which breakdown bone. Disturbances to this tightly orchestrated process are responsible for features of diseases such as osteoporosis and rheumatoid arthritis, which show excessive bone breakdown, or ankylosing spondylitis, where abnormal bone growth occurs.
The most commonly used osteoporosis therapies (bisphosphonates) target osteoclasts to prevent further bone loss. Although there are new 'anabolic' agents that can promote new bone formation, these have limitations in their clinical use, with teriparatide (parathyroid hormone, or PTH) only being effective for 24 months and romosozumab (anti-sclerostin antibody) being associated with cardiovascular events.
Therefore, there is a clear case for developing new therapies to stimulate bone repair in age-related musculoskeletal diseases, of which osteoporosis is the most common.
Dr James Edwards from NDORMS collaborated with researchers led by Dr Helen McGettrick and Dr Amy Naylor, including Dr Jonathan Lewis and Ms Kathryn Frost, from the Institute of Inflammation and Ageing at the University of Birmingham to investigate the potential therapeutic impact of PEPITEM in these disease states.
The research findings demonstrated that PEPITEM regulates bone remodelling and that increasing the amount present in the body stimulates bone mineralisation in 'young bones' that are not in a diseased or pre-osteoporotic state, and that this translates to an increase in bone strength and density similar to current standard of care drugs (bisphosphonates and PTH).
However, the key test for a potential new therapeutic is its ability to target the natural repair process that is compromised by age, or inflammatory disease. Here the researchers showed that giving additional PEPITEM limits bone loss and improves bone density in models of the menopause, which is a common trigger for osteoporotic bone loss in humans. Their studies also showed similar findings in models of inflammatory bone disease (arthritis), where PEPITEM significantly reduced bone damage and erosion.
James said: 'This work highlights the important role the immune system plays in the maintenance of healthy bone mass throughout life, and importantly, how this newly identified endogenous protein might be used as a new therapeutic option to protect against excessive bone loss.'
These findings were underscored by studies using human bone tissue, harvested from older patients during joint surgery. These studies showed cells from older individuals respond to PEPITEM, significantly increasing the maturation of osteoblasts, and their ability to produce and mineralise bone tissues.