Naturally occurring osteoarthritis in male mice with an extended lifespan.

Aim: The purpose of this study was to evaluate whether pharmacologic treatments or genotypes shown to prolong murine lifespan ameliorate the severity of age-associated osteoarthritis.Materials and Methods: Male UM-HET3 mice were fed diets containing 17-α-estradiol, acarbose, nordihydroguaiaretic acid, or control diet per the National Institute on Aging Interventions Testing Program (ITP) protocol. Findings were compared to genetically long-lived male Ames dwarf mice. Stifles were analyzed histologically with articular cartilage structure (ACS) and safranin O scoring as well as with quantitative histomorphometry.Results: Depending on the experimental group, ITP mice were between 450 and 1150 days old at the time of necropsy and 12-15 animals were studied per group. Two age groups (450 and 750 days) with 16-20 animals per group were used for Ames dwarf studies. No differences were found in the ACS or safranin O scores between treatment and control groups in the ITP study. There was high variability in most of the histologic outcome measures. For example, the older UM-HET3 controls had ACS scores of 6.1 ± 5.8 (mean±SD) and Saf O scores of 6.8 ± 5.6. Nevertheless, 17-α-estradiol mice had larger areas and widths of subchondral bone compared to controls, and dwarf mice had less subchondral bone area and width and less articular cartilage necrosis than non-dwarf controls.Conclusions: UM-HET3 mice developed age-related OA but with a high degree of variability and without a significant effect of the tested ITP treatments. High variability was also seen in the Ames dwarf mice but differences in several measures suggested some protection from OA.

A new era of genetic engineering for autoimmune and inflammatory diseases.

Chronic autoimmune and inflammatory diseases exhibit variable genetic factors. The tools for specific and efficient genetic engineering are developing at a dramatic pace and are now being applied to therapy of human diseases. Gene editing tools can be used to interdict the pathology of inflammation at multiple stages. Therapies utilizing genetically modified cells offer many potential advantages over traditional cellular therapy approaches. Monogenic autoinflammatory disease, loss of self-tolerance, autoimmune disease based in humoral immunity, and regenerative medicine for tissues deranged or destroyed by inflammation are potential pathologies that could be treated with therapies based in genetic editing technologies. In this review, we discuss the rapid evolution of technologies for genome editing and their applications for autoimmune and inflammatory diseases. We compare older-generation methods, including zinc-finger nucleases and transcription activator-like effector nucleases, with more-recently developed tools, mainly CRISPR/Cas9. Gene-editing tool delivery methods including viral vectors and non-viral technologies are summarized. Finally, pre-clinical experiments with gene editing for therapy of animal models of autoimmune and inflammatory disease, and initial experience with gene-edited cells in human autoimmunity are described. In this review, we discuss potential therapeutic uses of chimeric autoantigen receptor T cells and regulatory T cells for polygenic disease, genetically-modified hematopoietic stem and progenitor cell transplantation for monogenic disease, and modified induced pluripotent stem cells for regenerative medicine.