While perlecan is known to have pro-angiogenic functions in vivo, its C-terminal bioactive fragment, endorepellin, is an inhibitor of angiogenesis. Furthermore, the LG3 peptide, originally discovered in the urine of end-stage renal failure patients, has been characterised as the anti-angiogenic moiety of endorepellin. More recently, Chang et al. reported that conditioned media from the malignant breast cancer cell line, Hs578T, was found to have lower levels of LG3 peptide compared to the non-tumour breast cell line Hs578Bst. Moreover, these authors found that breast cancer patients had lower levels of circulating LG3 peptide compared to healthy volunteers and therefore proposed that low circulating LG3 peptide might be a potential biomarker of breast cancer. It is important to note here that our data may provide a different interpretation to the results reported by Chang et al., in that it is possible that the healthy volunteers recruited for their study were simply more active than the cancer patients prior to sample collection. Moreover, it is unlikely that one will observe lower levels of circulating LG3 in cancer patients if their tumour is secreting lower levels than the rest of the body, as suggested by the authors finding that breast cancer cells produced lower levels of LG3 in vitro. Chang et al. also noted that the only other studies which had described altered LG3 peptide levels were associated with urine analysis of patients with end stage renal failure and in amniotic fluid during premature foetal membrane rupture in pregnant women. Our data provides evidence for a potential additional explanation for the appearance of the LG3 peptide in urine. Clearly the exact nature and circumstances surrounding the alteration to circulating and urinary LG3 peptide or endorepellin requires further investigation. In further support of our data, the LG3 peptide is known to be proteolytically released from endorepellin and perlecan by both bone morphogenetic protein�C1 /Tolloid like Metalloprotease and caspase-3 mediated Cathepsin-L mechanisms. Recent studies have demonstrated that BMP-1 is released from cartilage explants following exposure to mechanical injury or to either of the inflammatory cytokines tumour necrosis factor-a or interleukin-1b. Both of these cytokines are found in rheumatoid and osteoarthritic synovial fluid and have both been shown to LY2109761 stimulate the expression of cathepsins in endothelial cells, macrophages and smooth muscle cells. Thus, the mediators of two of the known mechanisms of LG3 peptide R428 liberation are present and active in the articular cartilage/ synovial environment and/or musculoskeletal tissues generally.