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.
Sugimoto H, Yang C, LeBleu VS, Soubasakos MA, Giraldo M, Zeisberg M, et al. BMP-7 functions as a novel hormone to facilitate liver regeneration. FASEB J 2007;21:256–264. (Reprinted by permission.)
Kinoshita K, Iimuro Y, Otogawa K, Saika S, Inagaki Y, Nakajima Y, et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut; November 24, 2006, Epub ahead of print.
Bone morphogenetic protein-7 (BMP-7), also termed osteogenic protein-1 (OP-1), was originally identified in tryptic peptides that were generated from an enriched bovine osteogenic protein preparation.1 In mice, deficiency of BMP-7 leads to severe impairment of organ development, resulting in perinatal death.2 BMP-7 belongs to the transforming growth factor-β (TGF-β) superfamily and counteracts several TGF-β–induced, profibrogenic events that contribute to accumulation of extracellular matrix in mesenchymal cells.3 Molecular evidence revealed that BMP-7 is an endogenous antagonist of TGF-β1 and that supplementation with BMP-7 suppresses fibrogenesis in experimental models of renal disease and inhibits tubular epithelial-to-mesenchymal transition.4 Both BMP-7 and TGF-β1 bind to distinct type II receptors, which then associate and activate specific type I receptors that are commonly known as activin-like kinase (ALK) receptors. Once activated, the BMP receptors induce phosphorylation and activation of receptor-regulated Smads (R-Smads), namely Smad1, Smad5, and Smad8, whereas the activation of TGF-β1 receptors results in phosphorylation of Smad2 and Smad3 (Fig. 1). Subsequently, the R-Smads heterooligomerize with Smad4, translocate into the nucleus, and stimulate target gene expression. The signals are suppressed by the inhibitory Smad6 and Smad7 that interfere with R-Smad activation and their association with Smad4.
This complex signaling network is composed of different opposing ligands, receptors, and downstream signaling molecules offers a multitude of possibilities for therapeutic interventions when altered activities of either TGF-β1 or BMP-7 is the rationale of a disease.
Two recent studies provide experimental proof-of-principle for the therapeutic potential of BMP-7 in models of liver injury. Sugimoto and co-workers performed an extensive series of experiments investigating the therapeutic effects of recombinant BMP-7 on liver regeneration after partial hepatectomy in mice.5 Using this restoration model, the authors found that administration of BMP-7 significantly enhanced liver regeneration and functionality by triggering proliferation of hepatocytes. Conversely, liver regeneration was significantly impaired when endogenous BMP-7 was scavenged by administration of a soluble ALK3/Fc-chimera or a neutralizing antibody that was specific for BMP-7. Moreover, the authors further demonstrate that liver regeneration is associated with increased hepatic expression of ALK3 and nuclear translocation of Smad1 in hepatocytes, indicating active BMP signaling.
In the second study, Kinoshita and colleagues demonstrated that BMP-7 overexpression using an adenoviral vehicle attenuated the expression of collagen and α-smooth muscle actin in primary cultured hepatic stellate cells (HSCs) that was associated with an increase of Smad1/5/8 phosphorylation.6 In addition, ectopic expression of the transgene in a human HSC line (i.e. LX-2) was able to increase the expression of the inhibitor of differentiation-2 (Id-2). Id-2 is a key mediator in BMP-7 signaling that defines the potential of cell proliferation and opposes the fibrogenic activity of TGF-β1 in other systems.7 Consistently, BMP-7 induced hepatic Id-2 expression and reversed an already established liver fibrosis chemically induced by repeated application of thioacetamide in rats.
Collectively, these studies demonstrate that BMP-7 has impressive efficacy in attenuating experimental liver injury. In addition, a more clinical report recently shows that BMP-7 serum levels are elevated in patients with chronic liver disease, along with an increased expression of BMP-7 in hepatocytes.8 An up-regulation of endogenous BMP-7 in patients with liver cirrhosis fits very well to the proposed BMP-7 effects seen in vitro6 or in animal models.5 In contrast to the study of Kinoshita et al., however, BMP-7 was found to perpetuate the fibrogenic potential in a human HSC line that was immortalized by ectopic expression of a telomerase reverse transcriptase (hTERT).8 Therefore, it is possible that BMP-7 acts more ambiguously than the 2 studies may suggest, and future studies are clearly necessary to fully delineate the role of BMP-7 in the liver and define the exact conditions under which BMP-7 is the proposed regulator of liver health.
In conclusion, these highly encouraging studies show that BMP-7 is an interesting target molecule for the treatment of liver diseases. The previous finding that BMP-7, when administered systemically, is effectively taken up by the liver9 should make this cytokine even more attractive for clinical use. We hope the translation of the protective effects of BMP-7 into humans will result in improved therapeutics for patients suffering from liver dysfunction.