Journal of Theoretical Biology A mathematical model of signalling molecule-mediated processes during regeneration of osteochondral defects after chondrocyte implantation --Manuscript Draft-- Manuscript Number: JTB-D-23-00814R1

Kuiper, Jan-Herman; Campbell, Kelly; Naire, Shailesh

Abstract

Treating bone-cartilage defects is a fundamental clinical problem. The ability of damaged cartilage to self-repair is limited due to its avascularity. Left untreated, these defects can lead to osteoarthritis. Details of osteochondral defect repair are elusive, but animal models indicate healing occurs via an endochondral ossification-like process, similar to that in the growth plate. In the growth plate, the signalling molecules parathyroid hormone-related protein (PTHrP) and Indian Hedgehog (Ihh) form a feedback loop regulating chondrocyte hypertrophy, with Ihh inducing and PTHrP suppressing hypertrophy. To better understand this repair process and to explore the regulatory role of signalling molecules on the regeneration process, we formulate a mathematical model of osteochondral defect regeneration after chondrocyte implantation. The drivers of healing are assumed to be chondrocytes and osteoblasts, and their interaction via signalling molecules. We model cell proliferation, migration and chondrocyte hypertrophy, and matrix production and conversion, spatially and temporally. We further model nutrient and signalling molecule diffusion and their interaction with the cells. We consider the PTHrP-Ihh feedback loop as the backbone mechanisms but the model is flexible to incorporate extra signalling mechanisms if needed. Our mathematical model is able to represent repair of osteochondral defects, starting with cartilage formation throughout the defect. This is followed by chondrocyte hypertrophy, matrix calcification and bone formation deep inside the defect, while cartilage at the surface is maintained and eventually separated from the deeper bone by a thin layer of calcified cartilage. The complete process requires around 48 months. A key highlight of the model demonstrates that the PTHrP-Ihh loop alone is insufficient and an extra mechanism is required to initiate chondrocyte hypertrophy, represented by a critical cartilage density. A parameter sensitivity study reveals that the timing of the repair process crucially depends on parameters, such as the critical cartilage density, and those describing the actions of PTHrP to suppress hypertrophy, such as its diffusion coefficient, threshold concentration and degradation rate. Response to Reviewers: Reply to Reviewers We thank the reviewers for their careful reading of the manuscript and the insightful comments and suggestions they have provided. This has led to the manuscript being thoroughly revised both in the content and structure. The main revisions made are as follows. These are referred to by the corresponding section numbers and page numbers in the revised manuscript.

Citation

Kuiper, J., Campbell, K., & Naire, S. (in press). Journal of Theoretical Biology A mathematical model of signalling molecule-mediated processes during regeneration of osteochondral defects after chondrocyte implantation --Manuscript Draft-- Manuscript Number: JTB-D-23-00814R1. Journal of Theoretical Biology,

• Journal Article Type: Article
• Acceptance Date: Jun 7, 2024
• Deposit Date: Jun 7, 2024
• Print ISSN: 0022-5193
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Keywords: osteochondral defect; cartilage defect; Mathematical modelling; reaction-diffusion model; endochondral ossification
• Public URL: https://keele-repository.worktribe.com/output/847292
• Related Public URLs: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4616166