BMP-7 functions as a novel hormone to facilitate liver regeneration.

Bone morphogenic protein-7 (BMP-7) is a key protein involved in liver organogenesis and development. The physiological circulating concentration of BMP-7 is between 100 and 300 pg/ml. BMP-7 expression is absent in the liver, but the receptors for BMP-7 are present on adult hepatocytes. Therefore, we hypothesized that BMP-7 might function as an endogenous regulator of adult hepatocyte proliferation and liver homeostasis. Here, we demonstrate that neutralization of circulating endogenous BMP-7 results in significantly impaired regeneration of the liver after partial hepatectomy. Therapeutic administration of recombinant human BMP-7 (rhBMP-7) significantly enhances liver regeneration associated with accelerated improvement of liver function. Collectively, our results argue for the role of BMP-7 as a kidney- and bone-produced endogenous regulator of hepatocyte health.

Animal models of renal fibrosis.

Most of the present knowledge on pathomechanism of renal fibrosis is based on experimental studies with laboratory animals. Today, a variety of genetic and inducible animal models that mimic primary causes of human disease such as diabetes mellitus, glomerulonephritis, or lupus erythematodes are available. However, only few of these models progress consistently to interstitial fibrosis in the kidney involving interestitial fibrosis, tubular atrophy, and glomerulosclerosis, which are common features of renal fibrogenesis. In this chapter, the mouse models of nephrotoxic serum nephritis, COL4A3-deficiency, and unilateral urethral obstruction, which all result reliably into renal fibrosis, are described.

Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression.

Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.