Norman, BP 
ORCID: 0000-0001-9293-4852, Dillon, JP, Alkharabsheh, SM, Congues, F, Wilson, PJM, Davison, AS ORCID: 0000-0001-5501-4475, Chapman, E ORCID: 0000-0002-4398-1705, Baker, J, Coyle, S ORCID: 0000-0002-4761-9703, Probert, C ORCID: 0000-0003-0477-6714 et al (show 4 more authors)
(2025)
Identification of novel collagen breakdown products by human osteoclasts in vitro and in vivo
Jbmr Plus, 9 (12).
ziaf160-.
ISSN 2473-4039, 2473-4039
Abstract
Bone resorption involves dissolution of minerals and enzymatic degradation of bone matrix. The primary enzyme is cathepsin K but other proteases including matrix metalloproteinases are involved. Some cathepsin K cleavage products have been partially identified, including cross-linked telopeptides of type I collagen. Here, we aimed to characterize the entire complement of bone breakdown products resulting from osteoclast action under controlled conditions in vitro. We analyzed extracellular media from human osteoclasts cultured on dentin substrates, using untargeted liquid chromatography mass spectrometry. We discovered 22 breakdown products resulting from osteoclastic action. These products were peptide fragment sequences that mapped to various collagen proteins present in bone and dentin. Nine peptide fragments mapped exclusively to collagen I alpha-1 chain (COL1A1), the most abundant protein in bone. We subsequently detected 21 of the fragment products, initially observed in vitro, in human serum and/or urine. Consistent positive correlations were observed between the COL1A1-specific peptide fragments and established bone biochemical markers in serum and urine. Ten urine fragments and two serum fragments markedly increased (p <. 05) following total hip arthroplasty, capturing the transient local peri-prosthetic osteolysis observed in these patients (serum, n = 86 patients; urine, n = 83 patients). Among these candidate osteolytic markers, four (two COL1A1-specific products) showed decreases from baseline (p <. 05) in patients on denosumab (n = 10 patients). Additionally, two fragment peptides were higher (p <. 05, fold change >2) in urine from patients with bone metastasis (24 out of 112) among a lung cancer cohort. The range of collagen peptide fragments we discovered as a direct result of osteoclast activity indicates a complexity of bone resorption pathways not previously known, extending beyond the known proteolytic cleavage events in bone collagen proteins. Monitoring biofluid concentrations of these novel bone markers has the potential to capture multiple pathways of bone resorption activity beyond the existing assays based on cathepsin K.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | osteoclasts, resorption, peptide fragments, collagen |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Musculoskeletal & Ageing Science Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Women's & Children's Health |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 30 Oct 2025 10:03 |
| Last Modified: | 28 Feb 2026 17:26 |
| DOI: | 10.1093/jbmrpl/ziaf160 |
| Open Access URL: | https://doi.org/10.1093/jbmrpl/ziaf160 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3195092 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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