Accelerating functional gene discovery in osteoarthritis

Abstract

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.

Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

“…Our macroscopic assessment of the synovium found that the synovial membrane is thickened and dark red with obvious hyperemia on the synovial surface in the OA model group, which were alleviated by Ad-shIRAK4 treatment, although still more serious than that in the control group. The pathological score of synovitis was mainly evaluated from three aspects: the degree of proliferation of the synovitis lining layer, the degree of inflammation of the lining layer, and angiogenesis [ 15 ]. As shown in the result of H&E, compared with the control group, synovial hyperplasia severity, inflammatory cell infiltration, and angiogenesis were significantly aggravated in the OA model group.…”

“…To assess the degree of synovitis, sections of the sample were stained with Hematoxylin and Eosin (H&E) (Solarbio, China) by following the manufacturer’s standard instruction. The synovitis pathology score was determined primarily by three factors: the degree of proliferation of the synovitis lining layer, the degree of inflammation of the lining layer, and angiogenesis [ 15 ]. Synovitis severity was scored [(severity score = sum of pannus formation score (0–3) + synovial lining hyperplasia score (0–3) + sub-synovial inflammation score (0–3)].…”

The Bone Cartilage Interface and Osteoarthritis

“…Of mice and men? Some of the findings shown here might be duplicated in the smallest experimental mammals, and we cannot do fast gene experiments [ 47 , 76 ] in man and horse. But let us not think that we can do everything with mice.…”

“…The replica may be an internal cast , made by dissolving away the mineralized tissues from PMMA embedded material to show the fine space compartment occupied by ‘lacunae and canaliculi’ or—and usually much more usefully—the larger gauge blood vessel canals and marrow space in bone after dispersing the former [ 38 , 44 ]. It may alternatively be a one or a two stage replica of a surface—and that surface can be a wet surface—which is hugely advantageous in studying joint cartilage surfaces [ 47 ], but yet to be applied wholesale to large joints such as those of man and horse.…”

Imaging Study on Acupuncture Inhibiting Inflammation and Bone Destruction in Knee Osteoarthritis Induced by Monosodium Iodoacetate in Rat Model

“…2 While the knee joint is the most common site affected in OA. 3 The clinical manifestations of knee osteoarthritis (KOA) are joint pain, swelling, stiffness and even dyskinesia, 4,5 which affects the quality of life of patients and aggravates the medical burden of society. 6 Variety of physiological and mechanical factors affect the occurrence and development of KOA, involving age, sex, obesity, heredity trauma, and mechanical stress.…”