Bone-Enhancing Peptide Shows Promise as Therapeutic for Osteoporosis and MSK Disorders

Studies by University of Birmingham researchers suggest that a naturally occurring peptide known as PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration), could represent a promising potential therapeutic for osteoporosis and other disorders that feature bone loss, and offer distinct advantages compared with existing drugs.

PEPITEM was first identified in 2015 by University of Birmingham researchers. The team’s latest study has shown 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. Their reported study demonstrated that PEPITEM enhances bone mineralization, formation and strength, and reverses bone loss in animal models of disease.

Helen McGettrick, PhD, associate professor in inflammation and vascular biology said, “While the most commonly used drugs, bisphosphonates, work by blocking the action of osteoclasts, PEPITEM acts by swinging the balance in favor of bone formation, without impacting the ability of osteoclasts to resorb regions of damaged or weak bone tissue via normal bone remodeling.”

McGettrick is senior, and corresponding author of the team’s published paper in Cell Reports Medicine. In their paper, titled “Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss,” the investigators concluded, “… PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.”

Bone is constantly formed, reformed, and remodelled throughout life, and up to 10 percent of human bone is replaced annually through a complex interplay between two cell types— osteoblasts, which form bone, and osteoclasts, which breakdown bone. “Bone is a highly active organ, undergoing continuous osteoblast-induced bone formation and osteoclast-mediated bone resorption throughout life,” the authors explained. “The process of bone remodeling is orchestrated by cross-talk among osteoblasts, osteoclasts, and osteocytes acting in concert to maintain structural integrity, repair damage, and respond to changes in activity and load.”

Disturbances to this tightly orchestrated process are responsible for features of musculoskeletal (MSK) diseases such as osteoporosis, rheumatoid arthritis, and cancer-bone metastases, which show excessive bone breakdown, or ankylosing spondylitis, which is characterized by abnormal bone growth.

Osteoporosis is the most common bone disease globally, affecting over 54 million individuals in the U.S., and accounting for three million broken bones at a cost of $26 billion per annum, the team stated. “There are no cures for bone damage.” 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; PTH) only being effective for 24 months and romosozumab (anti-sclerostin antibody) being associated with cardiovascular events.

There is a clear case for developing new therapies to stimulate bone repair in age-related musculoskeletal diseases, including osteoporosis, the researchers pointed out. “… there is an urgent need to develop a new suite of therapies that lead to bone repair and regeneration in patients with MSK diseases to restore tissue homeostasis and functional integrity.” For their reported work the team—headed by McGettrick and Amy Naylor, PhD, Jonathan Lewis, PhD, and Kathryn Frost, from the Institute of Inflammation and Ageing at the University of Birmingham, and James Edwards, PhD, from Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford—set out to investigate the potential therapeutic impact of PEPITEM in these disease states.

PEPITEM is a naturally occurring peptide that is produced in the body and circulates at low levels. Through their studies in mice, the team demonstrated that PEPITEM regulates bone remodeling, and that increasing the amount present in the body stimulated bone mineralization in “young bones” that are not in a diseased or pre-osteoporotic state. “PEPITEM therapy significantly increased bone volume (BV/TV), trabecular number, and thickness in both the tibia and vertebrae of adult mice, indicating that PEPITEM promotes bone formation.” This, they found, translated to an increase in bone strength and density similar to that promoted by current standard of care drugs (bisphosphonates and PTH). “… the effect size for PEPITEM on BV/TV at two weeks is comparable to that seen following treatment with the bisphosphonate zoledronic acid for three weeks  or PTH for up to four weeks.Thus indicating PEPITEM is as efficient at inducing bone formation compared with current standard of care,” they noted.

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. Through their work the researchers showed that PEPITEM administration limited bone loss and improved bone density in ovariectomized animal models of the menopause, which is a common trigger for osteoporotic bone loss in humans. “Crucially, PEPITEM therapy halted any further bone loss following ovariectomy,” they wrote, and was effective at inducing bone formation by osteoblasts isolated from aged donors with osteoarthritis.” Their studies also showed similar findings in models of inflammatory bone disease (arthritis), where PEPITEM significantly reduced bone damage and erosion. “Similar findings were seen in an inflammatory model of bone erosion, where PEPITEM treatment significantly reduced bone damage in arthritic mice when compared with vehicle-treated animals.”

The findings in mice were supported by the results of work using human bone tissue, harvested from older patients during joint surgery. These studies showed that cells from older individuals respond to PEPITEM, significantly increasing the maturation of osteoblasts, and their ability to produce and mineralise bone tissues.

The team’s cell and tissue culture work further showed PEPITEM has a direct effect on osteoblasts to promote bone formation, by increasing the activity of osteoblasts rather than their number. Further experiments identified the NCAM-1 receptor as the specific receptor for PEPITEM on osteoblasts, and strongly suggested the NCAM-1- β-catenin signalling pathway is responsible for the upregulation of osteoblast activity. “PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength,” they wrote. This receptor, and the pathway, are distinct from PEPITEM receptors that have been previously described in other tissues.

The researchers also investigated PEPITEM’s effect on osteoclasts and bone resorption.  Here, mouse studies showed that PEPITEM significantly reduces the number of osteoclasts, leading to reduced bone mineral resorption. “Analysis of bone sections from mice treated with PEPITEM revealed a significant reduction in osteoclast numbers when compared with the treatment controls …” The researchers subsequently demonstrated that the reduction in osteoclast activity is the result of a soluble substance, osteoprotegerin (OPG) released locally in bone tissues by osteoblasts ‘activated’ by PEPITEM. The collective data, they stated, “…  indicate that in response to PEPITEM signaling through NCAM-1, osteoblasts release OPG, which in turn negatively regulate osteoclast numbers, leading to an overall reduction in bone resorption and increase in bone density.”

The study results, the team stated, “… highlight that PEPITEM could be used as an alternative and early clinical intervention to reverse the impact of age-related MSK diseases … As an endogenous osteogenic peptide with the capacity to regulate osteoblast-osteoclast coupling in health and disease, PEPITEM offers the real possibility for maintenance or restoration of bone homeostasis over the long-term to prevent osteoporosis and fragility fractures. For this to be realized, prolonged treatment protocols are now required in a variety of bone disease models to ascertain the quality of the bone formed in response to PEPITEM therapy.”