1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Osteoarthritis (OA) is a degenerative disease of synovial joints characterized by progressive loss of articular cartilage, subchondral bone remodeling, and intra-articular inflammation with synovitis that results in chronic pain and motor impairment. Despite the economic and health impacts, current medical therapies are targeted at symptomatic relief of OA and fail to alter its progression. Given the complexity of OA pathogenesis, we hypothesized that a combinatorial gene therapy approach, designed to inhibit inflammation with interleukin-1 receptor antagonist (IL-1Ra) while promoting chondroprotection using lubricin (PRG4), would improve preservation of the joint compared to monotherapy alone. Employing two surgical techniques to model mild, moderate and severe posttraumatic OA, we found that combined delivery of helper-dependent adenoviruses (HDVs), expressing IL-1Ra and PRG4, preserved articular cartilage better than either monotherapy in both models as demonstrated by preservation of articular cartilage volume and surface area. This improved protection was associated with increased expression of proanabolic and cartilage matrix genes together with decreased expression of catabolic genes and inflammatory mediators. In addition to improvements in joint tissues, this combinatorial gene therapy prolonged protection against thermal hyperalgesia compared to either monotherapy. Taken together, our results show that a combinatorial strategy is superior to monotherapeutic approaches for treatment of posttraumatic OA.

          Related collections

          Most cited references 27

          • Record: found
          • Abstract: found
          • Article: not found

          Bone remodelling in osteoarthritis.

          The classical view of the pathogenesis of osteoarthritis (OA) is that subchondral sclerosis is associated with, and perhaps causes, age-related joint degeneration. Recent observations have demonstrated that OA is associated with early loss of bone owing to increased bone remodelling, followed by slow turnover leading to densification of the subchondral plate and complete loss of cartilage. Subchondral densification is a late event in OA that involves only the subchondral plate and calcified cartilage; the subchondral cancellous bone beneath the subchondral plate may remain osteopenic. In experimental models, inducing subchondral sclerosis without allowing the prior stage of increased bone remodelling to occur does not lead to progressive OA. Therefore, both early-stage increased remodelling and bone loss, and the late-stage slow remodelling and subchondral densification are important components of the pathogenetic process that leads to OA. The apparent paradoxical observations that OA is associated with both increased remodelling and osteopenia, as well as decreased remodelling and sclerosis, are consistent with the spatial and temporal separation of these processes during joint degeneration. This Review provides an overview of current knowledge on OA and discusses the role of subchondral bone in the initiation and progression of OA. A hypothetical model of OA pathogenesis is proposed.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

            To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Osteoarthritis severity is sex dependent in a surgical mouse model.

              To investigate the role of sex hormones in cartilage degradation and progression of osteoarthritis (OA) in a murine model induced by destabilization of the medial meniscus (DMM). Accelerated OA development in mice was induced by transection of the menisco-tibial ligament, which anchors the medial meniscus to the tibial plateau. Intact male and female, and orchiectomized (ORX) male and ovariectomized (OVX) female mouse knee histology were compared for signs of OA following DMM. The effect of testosterone or estrogen addition in vivo was assessed in ORX males in the surgical OA model. OA severity was markedly higher in males than females after DMM. OVX females developed significantly more severe OA than control females. ORX males developed significantly less severe OA than control males. When ORX male mice were supplemented with exogenous dihydrotestosterone (DHT), the severity of OA was restored to the level experienced by the control male mice. Hip cartilage from mice of both sexes demonstrated similar spontaneous and interleukin-1alpha (IL-1alpha) induced proteoglycan (PG) release in vitro. DHT and 17-beta estradiol (E2) did not significantly alter the PG release pattern when supplemented to cartilage cultures of either sex. Sex hormones play a critical role in the progression of OA in the murine DMM surgical model, with males having more severe OA than females. Intact females had more OA than OVX females, indicating that ovarian hormones decrease the severity of OA in the female mice. Male hormones, such as testosterone, exacerbate OA in male mice as demonstrated by the fact that ORX mice experienced less OA than intact males, and that addition of DHT to ORX males was able to counteract the effect of castration and re-establish severe OA.
                Bookmark

                Author and article information

                Journal
                Human Gene Therapy
                Human Gene Therapy
                Mary Ann Liebert Inc
                1043-0342
                1557-7422
                February 2019
                February 2019
                : 30
                : 2
                : 225-235
                Affiliations
                [1 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
                [2 ]Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas.
                [3 ]H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas.
                [4 ]Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas.
                [5 ]Department of Pathology, Baylor College of Medicine, Houston, Texas.
                Article
                10.1089/hum.2018.106
                6383580
                30070147
                © 2019
                Product

                Comments

                Comment on this article