Item Details

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

Vanderman, Kadie S. (author)

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

title

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

type

Dissertation