Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis

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. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.

Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

“…Depletion of Phlpp1 activated Akt signaling, enhanced cell proliferation, and suppressed apoptosis, which likely promoted increased cellularity and cartilaginous matrix deposition in the NP region, preventing further progression of IDD. Small molecule Phlpp inhibitors have been synthesized and confirmed to improve cell survival and promote matrix production 57,58 . As Phlpp1 expression was increased with degeneration grades in human IVDs, local administration of Phlpp inhibitors via suitable biomaterials in herniated or mildly and moderately degenerated IVDs would alleviate the continued deterioration of IVD matrix and enhance cell survival via AKT signaling.…”

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

“…PHLPP1 is a serine/threonine phosphatase that modulates the activities of several kinases involved in maintaining anabolic functions of cartilage, including PKC, AKT, or p70 S6 kinase. Both ablation of Phlpp1 and pharmacological inhibition of PHLPP can block pain and cartilage degradation in the DMM model of surgically induced post‐traumatic OA . Furthermore, DNA methylation contributes to the regulation of SOST expression in OA chondrocytes, and changes in DNA methylation of the leptin promoter correlate with changes in leptin gene expression, contributing to alterations in MMP13 transcription in OA chondrocytes .…”

“…Both ablation of Phlpp1 160 and pharmacological inhibition of PHLPP can block pain and cartilage degradation in the DMM model of surgically induced post-traumatic OA. 161 Furthermore, DNA methylation contributes to the regulation of SOST expression in OA chondrocytes, 162 and changes in DNA methylation of the leptin promoter correlate with changes in leptin gene expression, contributing to alterations in MMP13 transcription in OA chondrocytes. 79 Moreover, SOD2 expression is decreased in end-stage OA cartilage, correlating with DNA methylation alterations of the SOD2 promoter; 163 and CpG demethylation in the NF-B enhancer at -5.8 kb of the NOS2 promoter correlates with its increased expression in OA.…”

Identification of core genes and prediction of miRNAs associated with osteoporosis using a bioinformatics approach

“…PHLPP2 exhibits nuclear localization and is expressed in numerous tissue types, including the small intestine, brain, bone marrow and ovaries (30). PHLPP inhibitors may relieve mechanical pain and slow cartilage degradation in osteoarthritic joints (31). Therefore, PHLPP2 has a potential regulatory role in OP and is a target for future research.…”