Novel Elements of the Chondrocyte Stress Response Identified Using an in Vitro Model of Mouse Cartilage Degradation

The
destruction of articular cartilage in osteoarthritis involves
chondrocyte dysfunction and imbalanced extracellular matrix (ECM)
homeostasis. Pro-inflammatory cytokines such as interleukin-1α
(IL-1α) contribute to osteoarthritis pathophysiology, but the
effects of IL-1α on chondrocytes within their tissue microenvironment
have not been fully evaluated. To redress this we used label-free
quantitative proteomics to analyze the chondrocyte response to IL-1α
within a native cartilage ECM. Mouse femoral heads were cultured with
and without IL-1α, and both the tissue proteome and proteins
released into the media were analyzed. New elements of the chondrocyte
response to IL-1α related to cellular stress included markers
for protein misfolding (Armet, Creld2, and Hyou1), enzymes involved
in glutathione biosynthesis and regeneration (Gstp1, Gsto1, and Gsr),
and oxidative stress proteins (Prdx2, Txn, Atox1, Hmox1, and Vnn1).
Other proteins previously not associated with the IL-1α response
in cartilage included ECM components (Smoc2, Kera, and Crispld1) and
cysteine proteases (cathepsin Z and legumain), while chondroadherin
and cartilage-derived C-type lectin (Clec3a) were identified as novel
products of IL-1α-induced cartilage degradation. This first
proteome-level view of the cartilage IL-1α response identified
candidate biomarkers of cartilage destruction and novel targets for
therapeutic intervention in osteoarthritis.