Research identifies new treatment options for bone restoration

Researchers in Birmingham have shown that PEPITEM, a naturally occurring peptide (small protein), offers unique benefits over traditional drugs and may be used as a new treatment for osteoporosis and other conditions involving bone loss.

2015 saw the discovery of PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) by researchers at the University of Birmingham.

According to data showing PEPITEM improves bone mineralization, formation, and strength while also reversing bone loss in animal models of disease, the most recent research, which was published today in Cell Reports Medicine, shows for the first time that PEPITEM could be used as a novel and early clinical intervention to reverse the effects of age-related musculoskeletal diseases.

Large grants from the Lorna and Yuti Chernajovsky Biomedical Research Foundation, which supports innovative research into the development of novel targeted medications to enhance health, and the Medical Research Council provided funding for the study. Versus Arthritis and the British Society for Research on Aging were among the other sponsors.

Throughout life, bone continually forms, reshapes, and is replenished by up to 10% a year. This process involves the intricate interaction of two cell types: osteoblasts, who create new bone, and osteoclasts, which break down existing bone. Diseases like ankylosing spondylitis, which causes aberrant bone formation, and osteoporosis and rheumatoid arthritis, which exhibit excessive bone disintegration, are caused by disruptions to this well-planned mechanism.

Bisphosphonates, the most widely used osteoporosis treatment, work by targeting osteoclasts to stop more bone loss. New ‘anabolic’ drugs that may stimulate the production of new bone are available, but their clinical use is limited. For example, teriparatide (parathyroid hormone, or PTH) is only effective for a period of 24 months, and romosozumab (an anti-sclerostin antibody) is linked to cardiovascular events.

Thus, there is a strong argument for creating novel treatments to promote bone regrowth in age-related musculoskeletal conditions, the most prevalent of which is osteoporosis. The potential therapeutic impact of PEPITEM in these disease states was investigated by researchers headed by Drs. Helen McGettrick and Amy Naylor. These researchers included Drs. Jonathan Lewis and Kathryn Frost from the University of Birmingham’s Institute of Inflammation and Ageing and Dr. James Edwards from the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences at the University of Oxford.

A naturally occurring short protein (peptide) called PEPITEM is created by the body and is present in all people at low concentrations.

The results of the study showed that PEPITEM controls the remodeling of bones and that elevating its level in the body promotes the mineralization of “young bones” that are not diseased or pre-osteoporotic. This results in an increase in bone density and strength that is comparable to that of current standard-of-care medications (bisphosphonates and PTH).

The capacity of a prospective novel treatment to specifically target the natural repair mechanism that is hampered by aging or inflammatory diseases, however, is the crucial test. Here, the researchers demonstrated that administering extra PEPITEM in animal models of menopause—a frequent cause for osteoporotic bone loss in humans—limits bone loss and enhances bone density. Similar results were also seen in models of inflammatory bone disease (arthritis), where PEPITEM greatly decreased erosion and destruction of the bone.

Studies using human bone tissue, taken from elderly individuals undergoing joint surgery, supported these conclusions. According to this research, PEPITEM has a considerable effect on the maturation of osteoblasts and their capacity to create and mineralize bone tissues in older adults’ cells.

Through an increase in osteoblast activity rather than quantity, their work with cell and tissue cultures has shown that PEPITEM directly affects osteoblasts to stimulate bone formation. Subsequent research revealed that the NCAM-1 receptor on osteoblasts is the particular receptor for PEPITEM, and it is very probable that the NCAM-1-b-catenin signaling pathway is in charge of the increased osteoblast activity. Compared to PEPITEM receptors that have been previously identified in other tissues, this receptor and its associated pathway are unique.

The impact of PEPITEM on osteoclasts and bone resorption was also examined by the researchers. Here, animal research has shown that PEPITEM dramatically lowers osteoclast counts, which in turn decreases bone mineral resorption. Subsequently, the researchers showed that a soluble material secreted locally in bone tissues by osteoblasts’stimulated’ by PEPITEM is responsible for the decrease in osteoclast activity.

Dr. Helen McGettrick stated: “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.”

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