Natural peptide shows potential as a new bone repair agent

Researchers from Birmingham have shown that PEPITEM, a naturally occurring peptide (small protein), holds promise as a new therapeutic agent for the treatment of osteoporosis and other bone-losing disorders, with clear advantages over existing drugs.

PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) was first identified in 2015 by researchers at the University of Birmingham.

Recent research published in the journal Cell Reports Medicine has shown for the first time that PEPITEM may be used as a novel and early clinical intervention to reverse age-related musculoskeletal diseases, with data demonstrating that PEPITEM enhances bone mineralization, formation and strength, and reverses bone loss in animal models of the diseases.

Bone is continually formed, rebuilt, and remodeled throughout life, with up to 10% of human bone replaced each year through a complex interaction between two types of cells—osteoblasts, which form bone, and osteoclasts, which destroy bone. Disruptions to this carefully coordinated process are responsible for the manifestations of diseases such as osteoporosis and rheumatoid arthritis, which are characterized by excessive bone destruction, or ankylosing spondylitis, which involves abnormal bone growth.

The most commonly used osteoporosis therapies (bisphosphonates) target osteoclasts to prevent further bone loss. Although there are newer "anabolic" agents that can promote new bone formation, they have limitations in clinical use, with teriparatide (parathyroid hormone, or PTH) only effective for 24 months and romosozumab (an anti-sclerostin antibody) associated with cardiovascular events.

Therefore, there is a clear need to develop new therapies to stimulate bone repair in age-related musculoskeletal diseases, of which osteoporosis is the most common.

Researchers led by Dr Helen McGettrick and Dr Amy Naylor, including Dr Jonathan Lewis and Catherine Frost from the Institute of Inflammation and Ageing at the University of Birmingham, and Dr James Edwards from the Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford, began investigating the potential therapeutic effects of PEPITEM in these conditions.

PEPITEM is a naturally occurring short protein (peptide) that is produced in the body and is found circulating in all humans at low levels.

The results of the study showed that PEPITEM regulates bone remodeling and that increasing its amount in the body stimulates bone mineralization in "young bones" that are not in a diseased or pre-osteoporotic state, and that this results in increased bone strength and density similar to current standard drugs (bisphosphonates and PTH).

However, a key test for a potential new therapeutic is its ability to target a natural repair process that is disrupted by age or inflammatory disease.

Here, the researchers showed that supplemental PEPITEM limited bone loss and improved bone density in animal models of menopause, a common cause of osteoporotic bone loss in humans. Their studies also showed similar results in models of inflammatory bone disease (arthritis), where PEPITEM significantly reduced bone damage and erosion.

These findings were supported by studies using human bone tissue extracted from elderly patients during joint surgery. These studies showed that cells from elderly people respond to PEPITEM by significantly increasing the maturation of osteoblasts and their ability to produce and mineralize bone tissue.

Their work with cells and tissue cultures showed that PEPITEM has a direct effect on osteoblasts, stimulating bone formation by increasing osteoblast activity rather than their number. Further studies identified the NCAM-1 receptor as a specific receptor for PEPITEM in osteoblasts and strongly suggested that the NCAM-1-β-catenin signaling pathway is responsible for increasing osteoblast activity. This receptor and pathway are distinct from previously described PEPITEM receptors in other tissues.

The researchers also examined the effects of PEPITEM on osteoclasts and bone resorption. Here, studies in mice showed that PEPITEM significantly reduced the number of osteoclasts, leading to a reduction in bone mineral resorption. The researchers subsequently demonstrated that the reduction in osteoclast activity was the result of a soluble substance secreted locally in bone tissue by osteoblasts “activated” by PEPITEM.

Dr Helen McGettrick said: "While the most commonly used drugs, bisphosphonates, work by blocking the action of osteoclasts, PEPITEM works by tipping the balance in favour of bone formation without affecting the ability of osteoclasts to resorb damaged or weak bone tissue through normal bone remodelling."

Helen Dunster, business development manager, who has overseen the intellectual property associated with PEPITEM for the past eight years, said: "PEPITEM is the subject of a number of patent families related to its activity in inflammation and inflammatory immune-mediated, bone and obesity-related diseases, as well as consisting of smaller PEPITEM pharmacophores."