Lead Optimization of Cathepsin K Inhibitors for the Treatment of Osteoarthritis

Ginnetti, Anthony T.; Paone, Daniel V.; Nanda, Kausik K.; Li, Jing; Busuek, Marina; Johnson, Scott Allen; Lü, Jun; Soisson, S.M.; Robinson, R.; Fisher, John W.; Webber, Andrea L.; Wesolowski, Gregg; Ma, Bennett; Duong, Le T.; Carroll, Steven S.; Burgey, Christopher S.; Stachel, Shawn J.

doi:10.2139/ssrn.4144318

SSRN Journal

2022

DOI: 10.2139/ssrn.4144318

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Lead Optimization of Cathepsin K Inhibitors for the Treatment of Osteoarthritis

Anthony T. Ginnetti

Daniel V. Paone

Kausik K. Nanda

et al.

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2024

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Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

Hu,

Williams,

Palladino

et al. 2024

Polymers

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Osteoarthritis (OA) is a chronic joint disease characterized by irreversible cartilage degradation. Current clinical treatment options lack effective pharmaceutical interventions targeting the disease's root causes. MMP (matrix metalloproteinase) inhibitors represent a new approach to slowing OA progression by addressing cartilage degradation mechanisms. However, very few drugs within this class are in preclinical or clinical trial phases. Hydrogel-based 3D in vitro models have shown promise as preclinical testing platforms due to their resemblance to native extracellular matrix (ECM), abundant availability, and ease of use. Metalloproteinase-13 (MMP-13) is thought to be a major contributor to the degradation of articular cartilage in OA by aggressively breaking down type II collagen. This study focused on testing MMP-13 inhibitors using a GelMA-alginate hydrogel-based OA model induced by cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The results demonstrate a significant inhibition of type II collagen breakdown by measuring C2C concentration using ELISA after treatment with MMP-13 inhibitors. However, inconsistencies in human cartilage explant samples led to inconclusive results. Nonetheless, the study highlights the GelMA-alginate hydrogel-based OA model as an alternative to human-sourced cartilage explants for in vitro drug screening.

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Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

Hu,

Williams,

Palladino

et al. 2024

Polymers

View full text Add to dashboard Cite

show abstract

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Lead Optimization of Cathepsin K Inhibitors for the Treatment of Osteoarthritis

Cited by 1 publication

References 6 publications

Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

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