Dataset Information

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

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.

SUBMITTER: Stone A

PROVIDER: S-EPMC6383580 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Stone Adrianne A Grol Matthew W MW Ruan Merry Z C MZC Dawson Brian B Chen Yuqing Y Jiang Ming-Ming MM Song I-Wen IW Jayaram Prathap P Cela Racel R Gannon Francis F Lee Brendan H L BHL

Human gene therapy 20181017 2

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, desig ...[more]

PMID: 30070147

Similar Datasets

Project description:The expression of Interleukin-1ß (IL-1ß) and its antagonist and Interleukin-1 receptor antagonist (IL-1Ra) are correlated with greater human intervertebral disc (IVD) degeneration, suggesting that elevated IL-1β activity promotes disc degeneration. Many in vitro studies support such a mechanistic relationship, whereas few in vivo investigations have been reported. The present study tests the effect of increased IL-1β activity on intervertebral disc in mice with an IL-1Ra gene deletion. IL-1Ra-/- mice and wild-type (WT) C57Bl6J mice were examined at 3 and 12 months of age. Caudal IVD segments were evaluated for disc degeneration by histopathology, functional testing, and inflammatory gene expression relevant to IL-1β pathways. To test differences in injury response, pinprick annular puncture was performed on IL-1Ra-/- and WT mice and evaluated similarly. IL-1Ra-/- IVDs had significantly worse histopathology at 3 months compared to WT controls, but not at 12 months. IL-1Ra-/- IVDs exhibited significantly more viscous mechanical properties than WT IVDs. qPCR revealed downregulation of inflammatory genes at 3 and 12 months in IL-1Ra-/- IVDs, with concomitant downregulation of anabolic and catabolic genes. Annular puncture yielded no appreciable differences between 2-week and 6-week post-injured WT and IL1-Ra-/- IVDs in histopathology or biomechanics, but inflammatory gene expression was sharply downregulated in IL-1Ra-/- mice at 2 weeks, returning by 6 weeks post injury. In the present study, IL-1Ra deletion resulted in increased IVD histopathology, inferior biomechanics, and transiently decreased pro-inflammatory cytokine gene expression. The histopathology of IL-1Ra-/- IVDs on a C57BL/6J background is less severe than a previous report of IL1Ra-/- on a BALB/c background, yet both strains exhibit IVD degeneration, reinforcing a mechanistic role of IL-1β signaling in IVD pathobiology. Despite a pro-inflammatory environment, the annular puncture was no worse in IL-1Ra-/- mice, suggesting that response to injury involves pathways other than inflammation. Overall, this study supports the hypothesis that IL-1β-driven inflammation is important in IVD degeneration.

Project description:ObjectivePlatelet-rich plasma (PRP) is an emerging therapeutic strategy for treatment of osteoarthritis (OA); however, there is a lack of preclinical and clinical evidence for its efficacy and its mechanism of action is unclear. In the current study, we utilized leukocyte poor-PRP (LP-PRP) and leukocyte rich-PRP (LR-PRP) to mimic clinical point of care formulations and assessed their potential to alter disease progression in a mouse model of post-traumatic OA.MethodThree-month-old wild-type male FVB/N mice received destabilization of the medial meniscus (DMM) surgery to induce OA. To assess the efficacy of LP-PRP and LR-PRP, mice were given intraarticular injections at 2-, 7- and 28-days post-surgery. Mice were then assessed at 5-, 9-, and 13-weeks post-surgery for changes in chronic pain using the hot plate nociceptive assay. At 14-weeks, OA pathogenesis was evaluated using histology and phase-contrast μCT.ResultsTreatment with LP-PRP and to a lesser extent LR-PRP preserved cartilage volume and surface area compared to phosphate-buffered saline (PBS) as measured by phase-contrast μCT. However, both treatments had higher Osteoarthritis Research Society International (OARSI) and synovitis scores compared to sham, and neither substantially improved scores compared to PBS controls. With respect to thermal hyperalgesia, PBS-treated mice displayed reduced latency to response compared to sham, and LR-PRP but not LP-PRP improved latency to response at 5-, 9- and 13-weeks post-surgery compared to PBS.ConclusionThe results of this study suggest that effects of PRP therapy on OA progression and disease-induced hyperalgesia may be leukocyte-dependent. And while LP-PRP and to a lesser extent LR-PRP protect from volume and surface loss, significant pathology is still seen within OA joints. Future work is needed to understand how the different components of PRP effect OA pathogenesis and pain, and how these could be modified to achieve greater therapeutic efficacy.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets