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Published on: March 18, 2022
Reduced response of human meniscal cells to Osteogenic Protein 1 during osteoarthritis and pro-inflammatory
K S Vanderman1, R F Loeser2, S Chubinskaya3
1Department of Orthopaedic Surgery, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Objective:
Many cell types lose responsiveness to anabolic factors during inflammation and disease. Osteogenic Protein 1 (OP1/BMP7) was evaluated for the ability to enhance extracellular matrix synthesis in healthy and OA meniscus cells. Mechanisms of cell response to OP1 were explored.
Design:
Meniscus and cartilage tissues from healthy tissue donors and osteoarthritis (OA) patients undergoing total knee arthroplasties were acquired. Primary cell cultures were stimulated with OP1 and/or inflammatory factors (IL1α, IL1β, or fibronectin fragments (FnF)) and cellular responses were analyzed by RT-qPCR and immunoblots. Frozen section immunohistochemistry (IHC) was conducted to assess OP1 and receptor proteins in normal and OA meniscus.
Results:
OP1 treatment of normal meniscus cells resulted in significant, dose-dependent increases in ACAN (aggrecan) and COL2A1, and decreased MMP13 gene transcription, while only ACAN was upregulated (P < 0.01) at the highest dose of OP1 in OA meniscus cells. OP1 induced significantly more ACAN gene transcription in normal meniscus than normal articular cartilage (P = 0.05), and no differences between normal and OA cartilage were detected. Receptor expression and kinetics of canonical signaling activation were similar between normal and OA specimens. Normal meniscus cells treated with inflammatory factors were refractory to OP1 stimulation. Smad1 phosphorylation at an inhibitory site was induced (P = 0.01 for both normal and OA meniscus) by inflammatory cytokine treatment.
Conclusions:
The meniscus demonstrates resistance to OP1 stimulation in OA and in the presence of inflammatory mediators. MAPK-mediated Smad1 linker phosphorylation is a possible mediator of the loss of anabolic extracellular matrix production in the inflammatory cytokine affected meniscus.
Insights
Osteogenic Protein 1 (OP1) enhances extracellular matrix synthesis in healthy meniscus cells but not in osteoarthritis (OA) meniscus cells, especially when exposed to inflammatory factors. Inflammatory mediators may block OP1
Area of Science:
- Biochemistry
- Cell Biology
- Orthopedics
Background:
- Cellular responsiveness to anabolic factors diminishes during inflammation and disease.
- Osteogenic Protein 1 (OP1/BMP7) is a key anabolic factor.
- Understanding meniscus cell response to OP1 is crucial for treating osteoarthritis (OA).
Purpose of the Study:
- To evaluate OP1's ability to enhance extracellular matrix synthesis in healthy and OA meniscus cells.
- To explore the mechanisms underlying cell response to OP1 in the context of inflammation.
Main Methods:
- Primary meniscus and cartilage cell cultures from healthy donors and OA patients were used.
- Cells were stimulated with OP1 and/or inflammatory factors (IL1α, IL1β, fibronectin fragments).
- Gene expression (RT-qPCR) and protein levels (immunoblots, IHC) were analyzed.
Main Results:
- OP1 significantly increased aggrecan (ACAN) and collagen type II alpha 1 (COL2A1) gene transcription in normal meniscus cells, while decreasing matrix metallopeptidase 13 (MMP13).
- In OA meniscus cells, only ACAN was upregulated by OP1 at the highest dose.
- Normal meniscus cells exposed to inflammatory factors were refractory to OP1, with inflammatory cytokines inducing inhibitory Smad1 phosphorylation.
Conclusions:
- Meniscus cells exhibit resistance to OP1 stimulation in OA and in the presence of inflammatory mediators.
- MAPK-mediated Smad1 linker phosphorylation is a potential mechanism for the loss of anabolic extracellular matrix production in inflamed meniscus cells.
