Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis

Soyun M. Hwang, Marina Feigenson, Dana L. Begun, Lomeli Carpio Shull, Kirsty L. Culley, Miguel Otero, Mary B. Goldring, Lauren E. Ta, Sanjeev Kakar, Elizabeth W. Bradley, Jennifer J. Westendorf

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects.

Original languageEnglish (US)
Pages (from-to)1487-1497
Number of pages11
JournalJournal of Orthopaedic Research
Volume36
Issue number5
DOIs
StatePublished - May 2018

Keywords

  • DMM surgery
  • Phlpp1
  • allodynia
  • post-traumatic osteoarthritis

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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  • Cite this

    Hwang, S. M., Feigenson, M., Begun, D. L., Shull, L. C., Culley, K. L., Otero, M., Goldring, M. B., Ta, L. E., Kakar, S., Bradley, E. W., & Westendorf, J. J. (2018). Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis. Journal of Orthopaedic Research, 36(5), 1487-1497. https://doi.org/10.1002/jor.23781