Bmp modulators in kidney disease

Career-Path Promotion Unit for Young Life Scientists, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Discovery medicine (Impact Factor: 3.63). 01/2012; 13(68):57-63.
Source: PubMed


Bone morphogenetic proteins (Bmps) are phylogenetically conserved signaling molecules that belong to the transforming growth factor beta superfamily. Although these proteins were first identified because of their ability to induce ectopic bone and cartilage formation, they are also involved in the cascades of body patterning and morphogenesis. Recently, several reports have indicated that the administration of pharmacological doses of Bmps inhibits and repairs acute and chronic renal injury in animal models. However, its mechanism of action and physiological function are not well understood. In addition, the exogenous administration of Bmps causes undesired side effects in other tissues, because Bmp receptors are widely expressed. The activities of Bmps are regulated by Bmp antagonists, which bind directly to Bmp and inhibit its binding to the receptor. Thus, the Bmp antagonists that modulate endogenous Bmp activities may be possible new therapeutic targets for kidney disease. In this review, we discuss recent findings related to Bmp antagonists modifying the function of Bmps in kidney disease.

8 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The outcome of patients suffering from spondyloarthritis is determined by chronic inflammation and new bone formation leading to ankylosis. The latter process manifests by new cartilage and bone formation leading to joint or spine fusion. This article discusses the main mechanisms of new bone formation in spondyloarthritis. It reviews the key molecules and concepts of new bone formation and ankylosis in animal models of disease and translates these findings to human disease. In addition, proposed biomarkers of new bone formation are evaluated and the translational current and future challenges are discussed with regards to new bone formation in spondyloarthritis.
    Rheumatic diseases clinics of North America 08/2012; 38(3):555-67. DOI:10.1016/j.rdc.2012.08.003 · 2.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal fibrosis is a major hallmark of chronic kidney disease, regardless of the initial causes, and prominent renal fibrosis predicts poor prognosis for renal insufficiency. Transforming growth factor (TGF)-β plays a pivotal role in the progression of renal fibrosis, and therapeutic interventions targeting TGF-β have been successful and well tolerated in animal models. However, these interventions might have adverse effects by inducing systemic inflammation due to the strong bifunctional role of TGF-β (pro-fibrotic and anti-inflammatory). This review of the current literature focuses on the inhibitors/antagonists of TGF-β, and discusses possible therapeutic approaches targeting them, describing the effectiveness of orally active bone morphogenetic protein 7 mimetics in reversing established fibrosis. It will conclude with a brief discussion of possible future directions for research.
    Nephrology Dialysis Transplantation 10/2012; 27(10):3686-91. DOI:10.1093/ndt/gfs381 · 3.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-β/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-β/Smad3 signalling and protects the kidney from TGF-β-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-β/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-β and BMP-7 in CKDs implies that targeting the TGF-β/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.
    Clinical Science 02/2013; 124(4):243-54. DOI:10.1042/CS20120252 · 5.60 Impact Factor
Show more