Pleiotropin (PTN) is a secreted heparin-binding peptide expressed in mesodermal and neuroectodermal cells during development, but rarely in adult tissues. Although PTN is abundant in fetal or juvenile cartilage, it is undectable in mature cartilage. However, PTN is re-expressed in chondrocytes in early stages of osteoarthritis where it is detectable in situ and in synovial fluids from patients. PTN enhances chondrogenesis by stimulation of extra-cellular matrix synthesis, reduction of degrading matrix metalloproteases and induction of their inhibitors; PTN also slightly reduces pro-inflammatory factors, such as nitric oxide and vascular endothelial growth factor. Furthermore, PTN stimulates chondrocyte clustering and proliferation. Thus, PTN appears to mediate repair and protective processes in osteoarthritic cartilage and appears to be a promising factor to treat osteoarthritis.