Peptide shows promise as therapeutic for bone loss disorders

Knee x-ray

Researchers have shown that a naturally occurring peptide holds promise as a new therapeutic for bone loss disorders and could have advantages over existing drugs.

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

The latest research shows 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. The data demonstrate that PEPITEM enhances bone mineralisation, formation and strength, and reverses bone loss in animal models of disease.

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.

Increase in bone strength and density

The research findings demonstrated that PEPITEM regulates bone remodelling. Increasing the amount present in the body stimulates bone mineralisation in ‘young bones’ that are not in a diseased or pre-osteoporotic state, which translates to an increase in bone strength and density similar to current standard of care drugs.

The researchers also showed that giving additional PEPITEM limits bone loss and improves bone density in animal 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. These findings were underscored by studies using human bone tissue, harvested from older patients during joint surgery.

Their cell and tissue culture work showed PEPITEM increases the activity of osteoblasts rather than their number. Further studies identified the NCAM-1 receptor as the specific receptor for PEPITEM on osteoblasts. Further mouse studies showed PEPITEM significantly reduces the number of osteoclasts, leading to reduced bone mineral resorption.

Dr Helen McGettrick, the Institute of Inflammation and Ageing at the University of Birmingham, said: “While the most commonly used drugs, bisphosphonates, work by blocking the action of osteoclasts, PEPITEM acts by swinging the balance in favour of bone formation, without impacting the ability of osteoclasts to resorb regions of damaged or weak bone tissue via normal bone remodelling.”

The research was conducted by teams at the University of Birmingham and University of Oxford, and funded by major grants from the Medical Research Council and the Lorna and Yuti Chernajovsky Biomedical Research Foundation.

Diana Spencer, Senior Digital Content Editor, DDW

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