Bone Density / Osteoporosis 45 min read January 27, 2026

PEPITEM Research: Osteoporosis and Bone Strength

PEPITEM enhances bone mineralization, formation, and strength, showing potential for treating age-related bone diseases.

PEPITEM Research: Osteoporosis and Bone Strength

PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration)

PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) was first identified in 2015 by researchers at the University of Birmingham. New research published in Cell Reports Medicine demonstrates for the first time that PEPITEM could be utilized as a novel early clinical intervention to mitigate the effects of age-related musculoskeletal diseases. The data indicates that PEPITEM enhances bone mineralization, formation, and strength, effectively reversing bone loss in animal models.

This research was supported by significant grants from the Medical Research Council and the Lorna and Yuti Chernajovsky Biomedical Research Foundation, which invests in research for developing new targeted medicines to improve health outcomes. Additional funding was provided by the British Society for Research on Ageing and Versus Arthritis.

Bone undergoes constant formation, reformation, and remodeling throughout life, with up to 10% of human bone being replaced annually. This process involves a complex interplay between osteoblasts, which form bone, and osteoclasts, which break down bone. Disruptions to this finely tuned process are responsible for diseases such as osteoporosis and rheumatoid arthritis, characterized by excessive bone breakdown, or ankylosing spondylitis, marked by abnormal bone growth.

PEPITEM's ability to enhance bone formation without adversely affecting osteoclast activity presents a promising therapeutic strategy. By promoting osteoblast activity and reducing osteoclast numbers via specific signaling pathways, PEPITEM has shown potential in increasing bone density and strength, suggesting its effectiveness as an early intervention for age-related bone diseases. This advancement could offer a new approach to maintaining bone health and preventing fractures, addressing a significant need in the treatment of osteoporosis and other musculoskeletal disorders.

Current osteoporosis therapies, such as bisphosphonates, primarily target osteoclasts to prevent further bone loss. While there are new anabolic agents available that promote new bone formation, their clinical use is limited. For example, teriparatide (parathyroid hormone, or PTH) is effective for only 24 months, and romosozumab (an anti-sclerostin antibody) has been linked to cardiovascular events. These limitations show the urgent need for developing new therapies to stimulate bone repair, especially in age-related musculoskeletal diseases like osteoporosis.

To address this need, a team of researchers led by Dr. Helen McGettrick and Dr. Amy Naylor, along with Dr. Jonathan Lewis and Ms. Kathryn 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, have been investigating the therapeutic potential of PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) in these conditions. Their research aims to explore whether PEPITEM can effectively stimulate bone repair and provide a new therapeutic avenue for treating osteoporosis and other age-related musculoskeletal disorders. By enhancing bone mineralization, formation, and strength, PEPITEM offers an exciting alternative that could overcome the limitations of existing therapies and significantly improve patient outcomes.

A key aspect of PEPITEM's potential as a therapeutic is its ability to target the natural repair processes impaired by age or inflammatory diseases. Researchers demonstrated that administering additional PEPITEM reduces bone loss and improves bone density in animal models of menopause, a common trigger for osteoporosis in humans. Similar benefits were observed in models of inflammatory bone disease, such as arthritis, where PEPITEM significantly reduced bone damage and erosion.

Further studies using human bone tissue from older patients undergoing joint surgery confirmed that cells from these individuals respond to PEPITEM by significantly increasing osteoblast maturation and their ability to produce and mineralize bone tissues. These findings show PEPITEM's potential as a novel therapeutic for treating osteoporosis and other age-related musculoskeletal disorders.

The research team's cell and tissue culture studies revealed that PEPITEM directly enhances osteoblast activity, promoting bone formation without increasing the number of osteoblasts. They identified the NCAM-1 receptor as the specific receptor for PEPITEM on osteoblasts and suggested that the NCAM-1-β-catenin signaling pathway is responsible for this upregulation. The NCAM-1-β-catenin signaling pathway involves the interaction between the neural cell adhesion molecule 1 (NCAM-1) and β-catenin, playing a crucial role in cell adhesion, signaling, and gene expression. NCAM-1 is a cell surface glycoprotein involved in cell-cell adhesion in various tissues, including bone. When PEPITEM binds to the NCAM-1 receptor on osteoblasts, it activates the β-catenin signaling pathway. β-catenin, a key protein in the Wnt signaling pathway, then translocates to the nucleus, where it influences the transcription of genes responsible for promoting osteoblast activity and bone formation. This pathway is distinct from other PEPITEM receptors found in different tissues and is critical for regulating bone remodeling and enhancing bone density.

Additionally, mouse studies showed that PEPITEM significantly reduces the number of osteoclasts, leading to decreased bone resorption. This reduction is due to a soluble substance released by PEPITEM-activated osteoblasts in bone tissues.

Dr. Helen McGettrick explained that while bisphosphonates inhibit osteoclasts to prevent bone loss, PEPITEM promotes bone formation by favoring osteoblast activity without hindering osteoclasts' natural bone remodeling processes.

1.PEPITEM Enhances Bone Formation and Strength Under Homeostatic Conditions

Initially we examined whether PEPITEM intrinsically regulated bone remodeling under basal conditions over a 2-week period (Figure 1A). PEPITEM therapy significantly increased bone volume (BV/TV), trabecular number, and thickness in both the tibia (Figures 1B–1D) and vertebrae (Figures 1F–1H) of adult mice, indicating that PEPITEM promotes bone formation. As expected, we observed a concomitant decrease in the gaps between individual trabeculae (trabecular separation [Figures 1E and I]), as the increased trabeculae created a denser, more interconnected trabecular network. Cortical bone turnover takes much longer than trabecular bone: ∼4–6 weeks.18 As expected, we observed no changes in the cortical bone following 2 weeks of PEPITEM treatment, but we did observe a significant increase in cortical bone parameters following 4 weeks of treatment (Figure S1). When comparing these findings with existing drugs targeting the bone, the effect size for PEPITEM on BV/TV at 2 weeks is comparable to that seen following treatment with the bisphosphonate zoledronic acid for 3 weeks19 or PTH for up to 4 weeks.20 Thus indicating PEPITEM is as efficient at inducing bone formation compared with current standard of care.

2. PEPITEM Acts Directly on Osteoblasts to Enhance Bone Mineralization and Limit Bone Resorption

Osteoblasts and osteoclasts work in concert to balance bone formation and resorption—thus an increase in trabecular bone could result from an increase in osteoblast activity or a decrease in osteoclast activity. Using alkaline phosphatase activity as an early marker of osteoblast maturation and alizarin red to visualize the later occurrence of bone mineralization, we next investigated the direct effect of PEPITEM on osteoblast function in vitro. PEPITEM significantly increased alkaline phosphatase activity in the murine ST2 osteoblast cell line (Figure 2A), primary murine calvarial osteoblasts isolated from male and female mice (Figures 2B and 2C) and the human hFOb 1.19 osteoblast cell line (Figure 2D) in culture. Of note, PEPITEM had no effect on cell number when compared with untreated controls (Figure 2E), indicating the changes in ALP are not due to more cells being present. This heightened PEPITEM-induced ALP expression resulted in significantly enhanced osteoblast mineral production over time, as detected by increases in alizarin red concentration (Figures 2F–2H). No changes were seen in osteoblast maturation or mineralization when cells were treated with an alternative 14aa peptide sequence within 14-3-3ξ (parent protein of PEPITEM, Figures 2A–2D, 2F, and 2G), indicating that it is PEPITEM itself that exhibits osteogenic properties. Supporting these in vitro findings, PEPITEM significantly enhanced mineral formation within intact metatarsal bones cultured ex vivo (Figures 2I and 2J). These findings demonstrate that PEPITEM acts directly on osteoblasts in the bone microenvironment to increase mineral deposition and together with the increases in bone formation rate and osteoid deposition observed in vivo collectively support the anabolic role of PEPITEM in bone formation. Several questions remain unanswered: what is the receptor for PEPITEM on osteoblasts and can PEPITEM influence osteoclast function?

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3. PEPITEM Interaction with NCAM-1 Leads to β-catenin Translocation in Osteoblasts

In the inflamed blood vascular bed, we have previously demonstrated that PEPITEM interacts with the adhesion molecule cadherin-15 (CDH15) on blood vascular endothelial cells to mediate its downstream immunomodulatory effects via sphingosine-1-phosphate (S1P).15 While primary murine and human osteoblasts express CDH15 transcript and protein (Figure S3A–S3C), treating primary murine osteoblasts with a CDH15 agonistic antibody had no effect on bone mineralization (Figure S3D), suggesting that CDH15 is not responsible for mediating the actions of PEPITEM on osteoblasts. Moreover, increasing concentrations of S1P caused a dose-dependent reduction in alkaline phosphate activity, and thus osteoblast activity (Figure S3E), in contrast to the increase observed with PEPITEM. Collectively, these data strongly indicate that the osteogenic actions of PEPITEM are triggered by a previously undescribed mechanism, which is distinct from the immunopeptide actions described for leukocyte trafficking during an inflammatory challenge.

To identify a PEPITEM receptor on osteoblasts, we used a biotin-conjugated PEPITEM to “fish” for potential binding partners on the cell surface of calvarial osteoblasts. This peptide showed pro-osteogenic activity, inducing osteoblast maturation and mineralization to a similar amount seen by native PEPITEM (Figure S4), indicating that biotinylation did not inhibit PEPITEM’s activity. PEPITEM-bound proteins eluted from osteoblast lysates were analyzed by mass spectrometry. Comparative analysis allowed exclusion of molecules identified in both control peptide and PEPITEM samples, and data were further filtered to include only those proteins associated with a membrane expression pattern using isoelectric point (Table S1). Of the top 10 hits, only two are known membrane proteins: NCAM-1 (CD56)21 and EHD2 (EH domain containing protein 2).22 Of these only NCAM-1 has previously been shown to be involved in osteoblastogenesis,21 although expression was transient and lost as MSC differentiate into osteoblasts.23,24 We detected both gene (Figure 3A) and protein expression of NCAM-1 in primary calvarial osteoblasts (Figures 3B and 3C), with western blot analysis revealing the presence of different NCAM-1 isoforms in osteoblasts—all of which increased in expression following PEPITEM treatment for 8 days (Figure 3C). To determine whether PEPITEM-enhanced osteoblast activity required NCAM-1, we treated osteoblasts with an NCAM-1 function blocking antibody or relevant immunoglobulin (Ig)G control in the presence of PEPITEM and assessed alkaline phosphatase activity. Inhibiting NCAM-1 blocked the effect of PEPITEM (Figure 3D), suggesting a role of NCAM-1 in mediating the effects of PEPITEM. Similarly, anti-NCAM-1 blocked PEPITEM-induced mineralization within intact metatarsal bones cultured ex vivo when compared with IgG1 treated controls (Figure 3E).

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4. PEPITEM Acts Indirectly on Osteoclasts to Reduce Bone Resorption

The interplay between osteoblast and osteoclast activity is carefully controlled, where increases in osteoblast activity are often matched with enhanced osteoclastogenesis (leading to increased bone resorption) to ensure balance is maintained. For this reason, it was necessary to assess the impact of PEPITEM on osteoclast function. Analysis of bone sections from mice treated with PEPITEM revealed a significant reduction in osteoclast numbers when compared with the treatment controls (Figure 5A), as measured by the presence of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Similarly, PEPITEM significantly reduced mineral resorption when whole murine bone marrow was cultured with osteoclast-stimulating factors (M-CSF and RANKL) on specialist hydroxyapatite-coated plates (Figure 5B). As the action of PEPITEM appeared to also influence osteoclast number and function, we subsequently assessed whether this was mediated by direct action on the osteoclasts or the consequence of paracrine signaling from a neighboring cell type (e.g., osteoblast) that would be present in the in vivo samples and in the whole bone marrow extract assay.

5. PEPITEM Induces Osteoblasts to Release a Soluble Mediator, which Inhibits Osteoclast Function

Osteoblasts can regulate osteoclastogenesis through paracrine signaling often through the RANKL-OPG axis. Osteoblasts secrete both RANKL and OPG, which have opposing functions—RANKL binds to its receptor (RANK) on monocytes to induce their differentiation to osteoclasts; while OPG acts as a decoy receptor for RANKL, inhibiting its binding to RANK and thus limiting osteoclast differentiation.32 Given this ability of osteoblasts to control osteoclastogenesis, we examined the possibility that the negative regulation of osteoclast function was due to production of a soluble agent released by osteoblasts in response to PEPITEM. To test this hypothesis, we collected the secretome/supernatant from PEPITEM-treated osteoblasts and transferred this onto osteoclast precursors (Figure 6A). Osteoclastogenesis in murine (Figure 6B) and human (Figure 6C) precursors was significantly inhibited in the presence of conditioned media from PEPITEM-treated osteoblasts, suggesting the presence of an inhibitory agent. When osteoblasts were treated with PEPITEM in the presence of Brefeldin A (a chemical inhibitor of the golgi), they were no longer able to generate the osteoclast inhibitory agent(s) (Figure 6D). Importantly, as PEPITEM does not influence osteoclasts directly (Figures 5C–5E), these data strongly indicate that osteoblasts are releasing a soluble mediator in response to PEPITEM that inhibits osteoclast function.

6. PEPITEM Reverses Bone Loss in Age-related Musculoskeletal Diseases

Osteoporosis is the most commonly occurring MSK condition, resulting in a net loss of cancellous bone and increased risk of fracture. To date, most osteoporosis medications target the activity of the osteoclast (e.g., bisphosphates, denosumab) to prevent further bone loss, but are unable to induce bone repair. Recent advances have enabled the development of anabolic agents, such as teriparatide (a parathyroid hormone mimic) and romosozumab, that can induce new bone formation but have limitations clinically—teriparatide is only effective for 24 months33 and romosozumab has been associated with cardiovascular events.34 Therefore, new drugs targeting the endogenous repair processes elicited by osteoblasts are urgently required. Given the pro-osteoblastogenic actions of PEPITEM revealed above, we sought to investigate the therapeutic efficacy of PEPITEM in a model of excessive bone loss.35

Osteoporosis onset is linked with menopause and the symptoms can be replicated _in vivo_ upon the removal of the ovaries, where bone loss is evident as early as 2 weeks post-surgery (Fig S7). PEPITEM therapy limited the amount of trabecular bone loss triggered by ovariectomy (Figure 7A) with comparable levels of bone volume density (BV/TV), trabecular number, and thickness in the tibia of PEPITEM-treated mice at 4 weeks and those at the start of the 2-week therapy regimen (Figures 7B–7D). In contrast, there was a significant reduction in all these parameters in mice treated with vehicle control.

As expected, we observed the reverse changes in trabecular separation (Figure 7E), indicating that PEPITEM therapy maintained a higher level of interconnectivity within the trabecular network during the onset of osteoporosis. 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 (Figure 7F). Using osteoblasts from aged patients (Table S5), we asked whether these cells were responsive to PEPITEM therapy. Crucially, PEPITEM significantly increased osteoblast maturation (Figures 7G and 7H) and mineralization (Figure 7I). These data highlight that PEPITEM could be used as an alternative and early clinical intervention to reverse the impact of age-related MSK diseases.

Reference:

Posted in: Bone Density / Osteoporosis

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