Emerging therapeutic targets for osteoarthritis

ABSTRACT

Introduction

Osteoarthritis is a heterogeneous joint disorder that lacks a clinically meaningful disease modifying drug. Animal models have been beneficial in understanding basic joint pathology and providing rationale for future clinical trials on identified targets. This review aims to discuss promising therapeutic targets of osteoarthritis that are currently in animal studies or early clinical trials.

Areas covered

PubMed was searched for articles published between 2017 and 2021 with the following terms: (osteoarthritis AND autophagy) OR (osteoarthritis AND senescence) OR (osteoarthritis AND TGFbeta) OR (osteoarthritis AND EGFR) OR (osteoarthritis AND Wnt/β-catenin) OR (osteoarthritis AND inflammation). Specific targets include the PI3/AKT/mTOR pathway, epidermal growth factor receptor, Toll-like receptors, and inflammatory interleukins, among others.

Expert opinion

In reviewing these targets, it is clear that the field of therapeutic targets for osteoarthritis has grown tremendously. We have gained a better understanding of previously identified targets, identified new targets, and have the opportunity to explore enhanced drug delivery via viral vectors. Regardless, translation to clinical benefits is still lacking in most cases. We propose that this may be due to the heterogeneous nature of the disease, lack of early diagnostic markers, mismatched preclinical animal models and clinical populations, and the complex role of many targets of interest.

KEYWORDS:

• Osteoarthritis
• DMOAD
• autophagy
• growth factors
• inflammation
• animal model

Article highlights

• OA is a whole joint disorder, with recent research increasingly examining the effects of therapeutic targets across the entire joint, as well as important tissue cross-talk

• Many key pathways act in a context-specific manner, such as TGFβ, EGFR, and Wnt signaling, presenting challenges for therapeutic targeting

• Clinical trials involving Wnt inhibition and viral vectors are promising for the field

• Utilizing a combination of therapeutic targets may be more beneficial than a mono therapy, as seen with the combination of IL-1Ra and Prg4

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

DMM Destabilizing medial meniscus

DMOAD Disease modifying osteoarthritis drug

ECM Extracellular matrix

EGFR Epidermal growth factor receptor

HDV Helper-dependent adenovirus

IL Interleukin

MMP Matrix metallopeptidase

OA Osteoarthritis

SASP Senescence-associated secretory phenotype

TGF Transforming growth factor

TLR Toll-like receptor

VEGF Vascular endothelial growth factor

Additional information

Funding

F Beier is the Canada Research Chair (Tier 1) in Musculoskeletal Research. Work in the Beier laboratory is supported by operating grants from the Canadian Institutes of Health Research (Grant #332438). E Hadzic is funded by the Arthritis Society Canada PhD Salary Award (#22-0000000154) with matched NIH funding, and a Transdisciplinary Training Award from the Bone and Joint Institute at Western University, Canada.