TLR4 antagonism provides short-term but not long-term clinical benefit in a full-depth cartilage defect mouse model

ABSTRACT

Purpose/Aim

Cartilage injury and subsequent osteoarthritis (OA) are debilitating conditions affecting millions worldwide. As there are no cures for these ailments, novel therapies are needed to suppress disease pathogenesis. Given that joint injuries are known to produce damage-associated molecular patterns (DAMPs), our central premise is that the Toll-like receptor 4 (TLR4) pathway is a principal driver in the early response to cartilage damage and subsequent pathology. We postulate that TLR4 activation is initiated/perpetuated by DAMPs released following joint damage. Thus, antagonism of the TLR4 pathway immediately after injury may suppress the development of joint surface defects.

Materials and Methods

Two groups were utilized: (1) 8-week-old, male C57BL6 mice treated systemically with a known TLR4 antagonist and (2) mice injected with vehicle control. A full-depth cartilage lesion on the midline of the patellofemoral groove was created in the right knee of each mouse. The left knee was used as a sham surgery control. Gait changes were evaluated over 4 weeks using a quantitative gait analysis system. At harvest, knee joints were processed for pathologic assessment, Nanostring® transcript expression, and immunohistochemistry (IHC).

Results

Short-term treatment with a TLR4 antagonist at 14-days significantly improved relevant gait parameters; improved cartilage metrics and modified Mankin scores were also seen. Additionally, mRNA expression and IHC showed reduced expression of inflammatory mediators in animals treated with the TLR4 antagonist.

Conclusions

Collectively, this work demonstrates that systemic treatment with a TLR4 antagonist is protective to further cartilage damage 14-days post-injury in a murine model of induced disease.

KEYWORDS:

• Toll-like receptor 4
• joint surface defects
• cartilage
• damage-associated molecular patterns
• MCP-1

Acknowledgments

The authors would like to thank Matthew Truelove, Sara Wist, and Margaret Campbell for their technical assistance. We would also like to acknowledge the intellectual contributions and discussions provided by Drs. Anna Plaas and John Sandy while this project was being crafted.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/03008207.2023.2269257

Additional information

Funding

This work was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535.