Chondrogenic progenitor cells promote vascular endothelial growth factor expression through stromal-derived factor-1

Objective: Vascular endothelial growth factor (VEGF) is elevated in joint fluids from patients diagnosed with osteoarthritis (OA). VEGF is known to contribute to vascular tidemark invasion and osteophyte formation, which are classic features of advanced OA. Among the factors that may drive VEGF accumulation in diseased joints, stromal cell-derived factor-1 alpha (SDF-1 alpha) is a likely culprit, as it is enriched in synovial fluids from osteoarthritic joints and is a potent inducer of VEGF expression. Chondrogenic progenitor cells (CPCs) that overexpress SDF-1 alpha are abundant in osteoarthritic cartilage, implicating them in elevating synovial SDF-1 alpha levels. Here we conducted a series of experiments to determine the potential for CPCs to stimulate VEGF expression via autocrine and paracrine mechanisms. Design: Immunohistochemistry, immunoblotting, and PCR were used to evaluate the effects of SDF-1 alpha on VEGF expression in CPCs and chondrocytes, and the effects of CPC-conditioned medium on chondrocytes. An SDF-1 alpha receptor antagonist and inhibitors of mitogen-activated protein kinases (MAPKs) were used to probe the pathway linking SDF-1 with VEGF expression in CPCs. Results: SDF-1 alpha and CPC-conditioned medium stimulated VEGF expression in chondrocytes. In both chondrocytes and CPCs, SDF-1 alpha stimulated increased VEGF expression via C-X-C chemokine receptor type 4 (CXCR4), a cell-surface SDF-1 alpha receptor. This response in CPCs is dependent on p38 MAPK activation, but not on ERK or c-Jun N-terminal kinase (JNK) activation. Conclusions: By secreting SDF-1 alpha, CPCs stimulate VEGF expression in nearby cells. The co-expression of SDF-1 and its receptor by CPCs indicates they are capable of self-sustained VEGF expression via an autocrine mechanism. (C) 2016 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.