On the predictive utility of animal models of osteoarthritis

Abstract

Animal models of osteoarthritis are extensively used for investigating disease pathways and for preclinical testing of novel therapies. Their predictive utility, however, has often been questioned, mainly because preclinical efficacy of novel therapeutics is poorly translated in clinical trials. In the current narrative review, we consider the preclinical models that were used to support undertaking clinical trials for disease-modifying osteoarthritis drugs, and compare outcomes between clinical and preclinical studies. We discuss this in light of the 1999 Food and Drug Administration draft guidelines for industry for use in the development of drugs, devices, and biological products intended for the treatment of osteoarthritis, which raised five considerations on the usefulness of osteoarthritis models. We systematically discuss what has been learnt regarding these five points since 1999, with emphasis on replicating distinct risk factors and subtypes of human osteoarthritis, and on comprehensive evaluation of the disease in animals, including pathology of all joint tissues, biomarker analysis, and assessment of pain and joint function. Finally, we discuss lessons learnt and propose some recommendations for how the evidence from preclinical research might be strengthened with a view to improving success in clinical translation.

The great debate: Should Osteoarthritis Research Focus on “Mice” or “Men”?

“…Thus drug development programs fail predominantly because their biological rationale, which is largely defined by preclinical research, was insufficient. The reasons underlying the inadequacy of this "starting evidence" are manifold and include issues with the conduct and reporting of pre-clinical research 9 . However rather than arguing for less pre-clinical research, the data on the reasons for drug development failures suggest greater emphasis on basic research to better understand disease pathophysiology and therapeutic target biology will improve subsequent clinical success.…”

Antinociceptive effect of clinical analgesics in a nonhuman primate model of knee osteoarthritis

“…However, few, if any, therapeutics developed in this manner have successfully completed double-blinded, placebo-controlled clinical trials (Huggins et al, 2012;Malfait and Little, 2015;Miller et al, 2014). While a number of issues have been identified that could underlie the limited translation of preclinical findings to a clinical treatment, one issue could be the use of rodents, which are phylogenetically distant to humans.…”

Metalloproteinases 1 and 13 as Markers of Destructive and Proliferative Processes in the Articular Cartilage in Experimental Osteoarthritis

“…В результате, активируются NF-kB рецепторы синовиальных фибробластов, что определя-ет высвобождение многих цитокинов, таких как ИЛ-6, ИЛ-10, GM-CSF, IL-8 и хемоаттрактант моноцитов, кото-рый, в свою очередь, играет значимую роль в актива-ции металлопротеиназ и обуславливает их высокую активность при остеоартрозе [6][7][8][9].…”