Objective: Osteoarthritis (OA) is a painful and crippling disease process, affecting the mobility and overall health of millions. Available treatments are aimed at symptomatic relief only and research to understand the disease process is sorely needed. Deletion of the Del1 gene has been shown to increase severity of osteoarthritis in knockout mice. We examine the intracellular pathways involved in the ability of DEL1 protein to protect chondrocytes from apoptosis and anoikis, and hypothesize that it functions via Integrin signaling.
Methods: Primary human chondrocytes were treated with various inducers of apoptosis, including anoikis, in the presence of added DEL1 or bovine serum albumin as control. Various inhibitors of Integrin binding, RGD peptides, were examined for their effect on DEL1 anti-apoptotic activity, which was measured by Caspase 3/7. Downstream signaling components of ERK and PI3/Akt pathways were tested for by immunoblotting.
Results: The addition of DEL1 protected chondrocytes from apoptosis through intrinsic and extrinsic pathways, and from anoikis. The effect of DEL1 was blocked by RGD peptides and by antibodies directed to Integrin aVb3, but not by controls or antibodies to Integrin a1.
Conclusion: DEL1 protected chondrocytes from apoptosis in response to activators of either the intrinsic or extrinsic pathways, and to anoikis. This effect is mediated primarily through Integrin aVb3. Signaling pathways involved in mediating the response were similar to those previously reported for Del1 in endothelial cells. This represents a therapeutic target for therapies to prevent cartilage degeneration in osteoarthritis and shines light on potential treatment for this debilitating disease.
