Bone Morphogenetic Proteins in Clinical Applications

Gautschi, Oliver; Frey, Sönke P.; Zellweger, René

doi:10.1111/j.1445-2197.2007.04175.x

Cited by 360 publications

(314 citation statements)

References 73 publications

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“…Recombinant human BMP-2 protein has been clinically used to enhance bone healing 18,27,28 Although our study did not find a significant difference in TGF-β1 or BMP-2 levels between normal union and nonunion groups which is consistent with previously reported findings, however we found a delayed maximal peak for both TGF-β1 and BMP-2 proteins in nonunion patients as compared to the normal union patients. The peak plasma value of TGF-β1 at 2-week may be explained by the fact that TGF-β1 is released from the granules of platelets during the clotting process soon after trauma 31 .…”

Section: Discussionsupporting

confidence: 92%

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing

et al. 2017

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Background:The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. Materials and Methods:We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA.Results: TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. Conclusion:The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management. (J Nippon Med Sch 2017; 84: 12 18)

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Section: Discussionsupporting

confidence: 92%

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing

et al. 2017

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“…Bmpr1a is a type I receptor that has a high affinity for BMP2 (26) and BMP4 (27), which are expressed in bone. BMPs have been shown to exhibit potent osteogenic activity in vitro (28), and the constitutive activation of BMPs or exogenous application of BMPs can induce ectopic bone formation in vivo (29). Therefore, Bmp4 mRNA showed a rhythmic expression pattern as well as the circadian clock gene Per2 in osteoblasts, which indicated that circadian oscillators regulate Bmp4 expression and may modulate diverse physiological processes in bone metabolism.…”

Section: Discussionmentioning

confidence: 99%

α1-Adrenergic Receptor Signaling in Osteoblasts Regulates Clock Genes and Bone Morphogenetic Protein 4 Expression through Up-regulation of the Transcriptional Factor Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding Protein 4 (E4BP4)

Hanabusa

Tanaka

Togari

2014

Journal of Biological Chemistry

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Background:The physiological role of ␣1-adrenergic receptor (AR) signaling in bone is largely unknown. Results: ␣1-AR signaling negatively regulates Bmp4 expression by up-regulating the transcriptional factor Nfil3/E4BP4 in osteoblasts. Conclusion: ␣1-AR signaling regulates clock genes and Bmp4 expression in osteoblasts. Significance: The regulation of clock genes by ␣1-AR signaling in osteoblasts may contribute to the physiological significance of the circadian clockwork in bone metabolism.

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“…BMPs have demonstrated clinical utility for bone regeneration and are available commercially and used therapeutically in open fractures of long bones, nonunions, and spinal fusion. (13) However, this process appears to be rather inefficient because large amounts of BMPs have to be applied to achieve beneficial effects. This might be due at least in part to the fact that BMPs induce expression of the BMP antagonist noggin, (14,15) providing a negative-feedback loop to hamper BMP activity and as a consequence clinical efficacy.…”

mentioning

confidence: 99%

Biphasic effects of transforming growth factor β on bone morphogenetic protein–induced osteoblast differentiation

Gorter

Dinther

Korchynskyi

et al. 2010

Journal of Bone and Mineral Research

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Bone morphogenetic proteins (BMPs) exert an important role in skeletal development, adult bone homeostasis, and fracture healing and have demonstrated clinical utility for bone regeneration. However, BMPs fall short as regenerative agents because high doses need to be used to obtain therapeutic effects. Determining the molecular mechanisms controlling BMP-induced bone formation may lead to the development of more effective BMP-based therapies. To identify kinases mediating BMP-induced osteoblast differentiation, we performed an siRNA screen to find kinases modulating BMP-6-induced alkaline phosphatase (ALP) activity. Surprisingly, although transforming growth factor b (TGF-b) generally is considered to antagonize BMP-induced osteoblast differentiation, C2C12 cells transfected with siRNAs targeting TGF-b receptors displayed reduced BMP-6-induced ALP activity. Furthermore, pharmacologic inhibitors blocking the TGF-b type I receptor impaired BMP-induced ALP activity in KS483 and C2C12 cells and mineralization of KS483 cells. Consistently, costimulation with BMPs and TGF-b further increased expression of osteoblast-specific genes, ALP activity, and mineralization of KS483 cells and primary mesenchymal stem cells compared with BMPs alone. The stimulatory and inhibitory effects of TGF-b were found to depend on timing and duration of the costimulation. TGF-b inhibited BMP-induced activation of a BMP-Smaddependent luciferase reporter, suggesting that the stimulatory effect of TGF-b is not due to increased BMP-Smad activity. TGF-b also inhibited the BMP-induced expression of the BMP antagonist noggin and prolonged BMP activity. In conclusion, TGF-b, besides acting as an inhibitor, also can, by dampening the noggin-mediated negative-feedback loop, enhance BMP-induced osteoblast differentiation, which might be beneficial in fracture healing. ß

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Bone Morphogenetic Proteins in Clinical Applications

Cited by 360 publications

References 73 publications

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing

α1-Adrenergic Receptor Signaling in Osteoblasts Regulates Clock Genes and Bone Morphogenetic Protein 4 Expression through Up-regulation of the Transcriptional Factor Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding Protein 4 (E4BP4)

Biphasic effects of transforming growth factor β on bone morphogenetic protein–induced osteoblast differentiation

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