Wnt10b and Dkk-1 gene therapy differentially influenced trabecular bone architecture, soft tissue integrity, and osteophytosis in a skeletally mature rat model of osteoarthritis

Jeffrey B. Mason, Brittney L. Gurda, Kurt D. Hankenson, Lindsey R. Harper, Cathy S. Carlson, James M. Wilson, Dean W. Richardson

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1 Scopus citations

Abstract

Aims: Our goals in the current experiments were to determine if (a) upregulation of Wnt signaling would induce osteoarthritis changes in stable stifle joints and (b) if downregulation of Wnt signaling in destabilized joints would influence the progression of OA. Methods: At 37 weeks of age, rats were injected in the stifle joint with a recombinant adeno-associated viral vector containing the Wnt-inhibitor Dkk-1 or a Wnt10b transgene. At 40 weeks of age, rats underwent surgical destabilization of the joint. At 50 weeks of age, stifle joints were submitted for micro-computed tomography and histopathological analysis. Results: Injection of either Wnt10b or Dkk-1 transgenes in stable joints improved bone architectural parameters, but worsened soft tissue integrity. Osteophytosis was decreased by Dkk-1, but unchanged by Wnt10b. Destabilization negatively influenced bone architecture, increased osteophytosis, and decreased soft tissue integrity. Dkk-1 exacerbated the negative effects of destabilization, whereas Wnt10b had little effect on these parameters. Osteophytosis was improved, whereas soft tissue integrity was worsened by both transgenes in destabilized joints. Conclusions: The Wnt-inhibitor Dkk-1 does not appear to completely inhibit the effects of Wnt signaling on bone remodeling. In vivo upregulation of Wnt10b and its inhibitor, Dkk-1, can produce both parallel or contrasting phenotypic responses depending on the specific parameter measured and the fidelity of the examined joint. These observations elucidate different roles for Wnt signaling in stable versus destabilized joints and may help to explain the conflicting results previously reported for the role of Dkk-1 in joint disease.

Original languageEnglish (US)
Pages (from-to)542-552
Number of pages11
JournalConnective Tissue Research
Volume58
Issue number6
DOIs
StatePublished - Nov 2 2017

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 1F32AR056936-01A2 to J.B.M. Research was also supported by The University of Pennsylvania Vector Core Facility and a grant to J.M.W. (NIH Grant 2-P30-DK047757-16). Recombinant AAV preparations were provided by the University of Pennsylvania Vector Core Facility (Philadelphia, PA). The content here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Dr. Serge Zolotukhin for help with the Wnt10b transgene, Dr. Marty Keough and Dr. Luk Vandenberghe for help with virus production, Dr. Shawn Terkhorn for help with the in vitro transgene assays, Dr. Julie Engiles for help with the osteophyte grading, Ms. Deirdre McMenamin and Ms. Christine Draper for technical assistance with the rats, Mr. Wei-Ju Louis Tseng for assistance with micro-CT data management, and Dr. Rusty Stott and Ms. Sarah Behunin with digital radiographs for verification of joint decalcification. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 1F32AR056936-01A2 to J.B.M. Research was also supported by The University of Pennsylvania Vector Core Facility and a grant to J.M.W. (NIH Grant 2-P30-DK047757-16). Recombinant AAV preparations were provided by the University of Pennsylvania Vector Core Facility (Philadelphia, PA). The content here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 1F32AR056936-01A2 to J.B.M. Research was also supported by The University of Pennsylvania Vector Core Facility and a grant to J.M.W. (NIH Grant 2-P30-DK047757-16). Recombinant AAV preparations were provided by the University of Pennsylvania Vector Core Facility (Philadelphia, PA). The content here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2017 Taylor & Francis.

Keywords

  • Cartilage
  • Wnt/Dkk-1 pathway
  • gene therapy
  • osteoarthritis
  • osteophyte

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