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EFFECTS OF OSTEOARTHRITIS AND INFLAMMATION ON MENISCUS CELL RESPONSE TO OSTEOGENIC PROTEIN 1 (OP1)

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title
EFFECTS OF OSTEOARTHRITIS AND INFLAMMATION ON MENISCUS CELL RESPONSE TO OSTEOGENIC PROTEIN 1 (OP1)
author
Vanderman, Kadie S.
abstract
The long term objective of this project was to determine the response to the Bone Morphogenic Protein (BMP) family member, Osteogenic Protein 1 (OP1/BMP7) in meniscus cells. We have focused on the meniscus, because this tissue is highly susceptable to injuries which often fail to heal and lead to osteoarthritis (OA). OA is driven by molecular inflammation which disrupts tissue homeostasis through the upregulation of catabolism (extracellular matrix breakdown) which outpaces anabolism (matrix synthesis). OP1 has been shown to be the most potent natural inducer of articular cartilage matrix synthesis. We chose to evaluate this growth factor for its ability to induce meniscus matrix synthesis during pro-inflammatory factor treatment and OA with the translational objective of assessing OP1 as a potential repair factor after trauma and/or disease of the meniscus. The first aim of this project was to compare the OP1 response of normal and OA menisci. We tested the hypothesis that OP1 stimulation of OA meniscus cells will result in reduced canonical BMP signaling and matrix synthesis compared to normal cells. Our results in normal meniscus cells showed that OP1 stimulated matrix expression and suppressed catabolic factor expression. However, OA meniscus cells were refractory to OP1, and insensitivity to OP1 could be induced in normal cells following treatment with pro-inflammatory factors. Our second aim was to determine the mechanism of OP1 insensitivity during pro-inflammatory cytokine stimulation. As the BMP transcription factor, Smad1, is a major regulatory target of signaling cross talk, we hypothesized that pro-inflammatory cytokine stimulation of normal and osteoarthritis meniscus cells will stimulate inhibitory phosphorylation of the Smad linker region (Ser206). We identified that such cytokine stimulation resulted in significantly increased Smad linker region phosphorylation at Serine 206, part of a MAP kinase phosphorylation consensus site shown to inhibit Smad1 activity. This work is the only identified study of OP1 to assess anabolic insensitivity and target a mechanism contributing to it in meniscal cells. The findings of this work indicate a target to restore anabolic sensitivity to OP1 and aid in the restoration of tissue homeostasis following inflammation.
subject
bone morphogenetic protein (BMP)
cytokine
extracellular matrix
meniscus
osteoarthritis
osteogenic protein 1 (OP1)
contributor
Ferguson, Cristin M (committee chair)
Willey, Jeffrey S (committee member)
Christ, George J (committee member)
Daniel, Larry W (committee member)
Register, Thomas C (committee member)
date
2016-01-11T09:35:27Z (accessioned)
2016-07-10T08:30:10Z (available)
2015 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2016-07-10 (terms)
identifier
http://hdl.handle.net/10339/57440 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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