The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage.

Abstract

Vascular endothelial growth factor (VEGF) has recently been shown to play an important role during endochondral bone formation in hypertrophic cartilage remodeling, ossification, and angiogenesis, but it is not expressed in normal adult cartilage. Since genes expressed during development often reappear in the disease state, we investigated whether VEGF and its receptors (VEGFRs) are expressed in osteoarthritic (OA) cartilage. VEGF production in OA cartilage from the tibial plateau was measured by enzyme-linked immunosorbent assay. Deposition of VEGF and VEGFR was determined by immunohistochemistry. Expression of messenger RNA for the different VEGF splice forms and for VEGFR was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Increased VEGF concentrations were measured in OA cartilage from the tibial plateau, while VEGF was almost undetectable in normal cartilage but could be immunostained within the intracellular and pericellular matrices of OA chondrocytes. In analyses of cartilage samples from all 10 OA patients evaluated, VEGF121 and VEGF189 were identified as the only VEGF splice forms expressed. RT-PCR and immunohistochemistry for VEGF in normal hyaline cartilage yielded negative findings. In addition to VEGF, VEGFR-2 (kinase domain region/fetal liver kinase 1), but not VEGFR-1 (fms-like tyrosine kinase 1), could be detected by RT-PCR in OA cartilage and immunostained on OA chondrocytes. Apart from its production in hypertrophic chondrocytes, VEGF is also produced in chondrocytes of OA cartilage. While the splice variant VEGF189 binds to extracellular matrix proteoglycans, VEGF121 is diffused freely. Both proteins should contribute to the inflammatory process by autocrine/paracrine stimulation of chondrocytes, chemotaxis of macrophages, and promotion of angiogenesis.