The ageing bone: PEPITEM as a novel inducer of bone repair

Frost, Kathryn ORCID: 0000-0001-8992-4637 (2025). The ageing bone: PEPITEM as a novel inducer of bone repair. University of Birmingham. Ph.D.

Frost2025PhD.pdf Text - Accepted Version Restricted to Repository staff only until 1 August 2026. Available under License All rights reserved. Download (15MB) | Request a copy

Abstract

Bone is a highly dynamic organ undergoing constant osteoblast-mediated bone formation and osteoclast-mediated bone resorption, allowing for balanced bone remodelling. This process is regulated by multiple endogenous factors, such as parathyroid hormone and oestrogen. Recently an endogenous peptide, known as PEPITEM has been shown to regulate bone remodelling through a dual action on osteoblasts and osteoclasts, making it a promising therapeutic for the treatment of bone loss in diseases such as osteoporosis.
In this thesis we expand on the current understanding of PEPITEM, investigating its molecular mechanism on osteoblasts and osteoclasts, whilst also exploring the therapeutic benefits of peptide memetics derived from PEPITEM. We hypothesised that PEPITEM is having direct actions on osteoblasts through membrane receptor signalling, causing changes in osteoblast maturation and osteoblast-osteoclast communication.
We identified through the use of ex vivo and both 2D and 3D in vitro experiments, that PEPITEM is able to act on osteoblasts to increase extracellular matrix production and mineralisation through actions on the membrane receptor, neural cell adhesion molecule 1 (NCAM-1). PEPITEM binding was shown to elicit increased -catenin signalling, resulting in increased osteoblast maturation and activity. NCAM-1 mediated activation of osteoblasts was also shown to increase secretion of anti-osteoclastogenic molecule osteoprotegerin (OPG), which mediates the indirect anti-os2teoclastogenic actions of PEPITEM.
Previous experiments showing PEPITEMs limited half-life led us to explore the bioactive residues present in the PEPITEM sequence, in order to explore the therapeutic potential of PEPITEM mimetics. Here we show that PEPITEM memetics are able to partially mimic PEPITEM actions both in vitro and in vivo. In vitro memetics were able to increase osteoblast maturation, however not all memetics were able to increase OPG secretion. Comparatively in vivo both memetics tested were able to increase bone formation and reduce osteoclast number during homeostasis increasing trabecular bone length. The bioactivity of these peptides was maintained during disease, where ovariectomised show reduced trabecular bone loss in response to peptide treatments.
This project offers new insights into how the endogenous peptide PEPITEM functions and its role in bone homeostasis and disease. The identification of the PEPITEM-NCAM-1 pathway enhances our understanding of osteoblast activity and opens up potential new avenues for therapeutic intervention. Additionally, the discovery of bio-active regions within the PEPITEM sequence, regions that retain partial PEPITEM function both in vitro and in vivo, provides further understanding of the peptide's mechanism. These findings suggest potential new therapeutic targets for bone loss, as these bio-active regions could enable less frequent treatments compared to the full PEPITEM peptide.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID McGettrick, Helen UNSPECIFIED UNSPECIFIED Naylor, Amy UNSPECIFIED UNSPECIFIED Edwards, James UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (former) > College of Medical & Dental Sciences
School or Department:	School of Infection, Inflammation and Immunology, Department of Inflammation and Aging
Funders:	Other
Other Funders:	The Lorna and Yuti Chernajovsky Biomedical Foundation, British Society for Research on Ageing
Subjects:	Q Science > QR Microbiology > QR180 Immunology
URI:	http://etheses.bham.ac.uk/id/eprint/15931

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