Natural peptide shows potential as 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 loss disorders, with clear advantages over existing drugs.

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

Recent studies published in Cell Reports Medicine show for the first time that PEPITEM could be used as a new 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 disease.

Bone is constantly being formed, remodeled and remodeled throughout life, and up to 10% of human bone is replaced annually through a complex interaction between two types of cells—osteoblasts, which form bone, and osteoclasts, which break down bone. Disturbances in this carefully coordinated process are responsible for 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 therapies for osteoporosis (bisphosphonates) target osteoclasts to prevent further bone loss. Although there are new "anabolic" agents that can promote new bone formation, they have limitations in clinical use, with teriparatide (a parathyroid hormone, or PTH) only effective for 24 months, and romosozumab (an anti-sclerostin antibody) associated with cardiovascular disease. -vascular events.

Consequently, 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 Aging 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 to investigate 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 people 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 leads to 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 the natural repair process that is compromised by age or inflammatory disease.

Here, researchers showed that administration of 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 removed from elderly patients during joint surgery. These studies showed that cells from older adults 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 the increase in osteoblast activity. This receptor and pathway is different from previously described PEPITEM receptors in other tissues.

Researchers also studied the effects of PEPITEM on osteoclasts and bone resorption. Here, studies in mice showed that PEPITEM significantly reduced the number of osteoclasts, leading to decreased bone mineral resorption. Subsequently, researchers demonstrated that the reduction in osteoclast activity is the result of a soluble substance released locally into 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 shifting the balance in favor of bone formation without interfering with the ability of osteoclasts to resorb damaged or weak bone tissue through normal bone remodeling."

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 immune-mediated inflammatory, bone and related with obesity diseases, as well as those consisting of smaller pharmacophores of PEPITEM."