Ligand-induced downregulation of receptors for TGF-beta in human osteoblast-like cells from adult donors

Gebken, J.; A, Feydt; Brinckmann, J; Notbohm, Holger; Muller, P.J.; Bätge, Boris

doi:10.1677/joe.0.1610503

Cited by 28 publications

(21 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As described previously in detail, human osteoblasts exhibit the property of markedly downregulating the number of cell surface receptors for TGF-ß after incubation with the ligand [24]. In order to investigate whether or not osteoblasts from donors with OI differ with respect to this adaptive response, cells from OI patients were preincubated for 18 h with 40 pM TGF-ß1 prior to bind-Gebken/Brenner/Feydt/Notbohm/ Brinckmann/Müller/Bätge ing studies with 125 I-TGF-ß1.…”

Section: Ligand-induced Downregulation Of Receptors For Tgf-ßmentioning

confidence: 75%

Increased Cell Surface Expression of Receptors for Transforming Growth Factor-β on Osteoblasts from Patients with Osteogenesis imperfecta

Gebken¹,

Brenner

A³

et al. 2000

Pathobiology

View full text Add to dashboard Cite

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder usually characterized by either a reduction in the production of normal collagen I or the synthesis of abnormal collagen. The variability in the clinical phenotype is not in each case sufficiently explained by the underlying mutation in the collagen I genes. Also, biochemical differences between mutant collagen from different tissues suggest additional regulatory mechanisms possibly involved in matrix deposition and maturation, two processes in which transforming growth factor-β (TGF-β) plays an important role. We, therefore, studied the cell surface expression and functional properties of TGF-β receptors I, II and III on osteoblasts from a group of OI patients compared to healthy controls. Receptor number and affinity were determined by Scatchard analysis of binding data and TGF-β receptor II gene expression was assessed by RT-PCR. Ligand-induced downregulation of TGF-β receptors was analyzed to demonstrate the dynamic response to exogenous stimuli. All experiments were performed in parallel in human osteoblastic cells from OI patients and from age-matched controls. TGF-β receptors I, II and III (betaglycan) were present on osteoblasts from both healthy donors and OI patients. The receptor numbers were significantly higher (29,000 per cell) on OI osteoblasts than on age-matched control osteoblasts (12,000 per cell) in spite of similar steady state levels for TGF-β receptor II mRNA in OI and control cells. Furthermore, receptor affinity was not significantly different in OI osteoblasts (181 vs. 177 nM^–1), and the receptor number did not depend on the culture substrate. With respect to dynamic adaption, ligand-induced downregulation of TGF-β receptors was reduced in OI osteoblasts. In conclusion, the human osteoblastic cells from patients with OI investigated all have an elevated number of cell surface receptors for TGF-β, without any evidence for a transcriptional regulation of TGF-β receptor II. On the functional level, there is some evidence for an impaired adaptive behavior of receptor presentation, whereas receptor affinity is unchanged.

show abstract

Section: Ligand-induced Downregulation Of Receptors For Tgf-ßmentioning

confidence: 75%

Increased Cell Surface Expression of Receptors for Transforming Growth Factor-β on Osteoblasts from Patients with Osteogenesis imperfecta

Gebken¹,

Brenner

A³

et al. 2000

Pathobiology

View full text Add to dashboard Cite

show abstract

“…3D). It is believed that overdoses of growth factors can suppress expression of their own receptors 34,35 possibly through enhanced receptor degradation. 36 Futureinquiries into changes in receptor numbers due to their interactions with other environmental factors such as ECM 37 are necessary.…”

Section: Discussionmentioning

confidence: 99%

“…One explanation is that elongated cells at the periphery of TGF-b1 constructs expressed a minimal level of TGF-bRII (Fig. 3D), the molecule associated with the initial binding of TGF-b and triggering subsequent intracellular reactions, 35 so they were blocked from receiving TGF-b1 signals, and thus acted like normal chondrocytes. Supportively, a recent study showed that high doses of TGF-b (10 ng/mL) can suppress collagen I synthesis by fibroblasts via upregulation of CUX1.…”

Section: Discussionmentioning

confidence: 99%

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

Yang

Barabino

2013

Tissue Engineering Part A

View full text Add to dashboard Cite

Successful tissue-engineering strategies for cartilage repair must maximize the efficacy of chondrocytes within their limited life span. To that end, the combination of exogenous growth factors with mechanical stimuli holds promise for development of clinically relevant cartilage tissue substitutes. The current study aimed to determine whether incorporation of transient exposure to growth factors into a hydrodynamic bioreactor system can improve the functional maturation of tissue-engineered cartilage. Chondrocyte-seeded polyglycolic acid scaffolds were cultivated within a wavy-walled bioreactor that imparts fluid flow-induced shear stress for 4 weeks. Constructs were nourished with 100 ng/mL insulin-like growth factor-1 (IGF-1) or 10 ng/mL transforming growth factor-b1 (TGF-b1) either for the first 15 days of the culture (transient) or throughout the entire cultivation (continuous). Transiently treated constructs were found to exhibit better functional properties than continuously nourished constructs. The limited development of engineered tissues continuously stimulated by IGF-1 or TGF-b1 was related to massive growth factor leftovers in the environments that downregulated the expression of the associated receptors. Treatment with TGF-b1 eliminated the formation of a fibrous capsule at the construct periphery possibly through suppression of Smad3 phosphorylation, yielding constructs with greater homogeneity. Furthermore, TGF-b1 reversely regulated Smad2 and Smad3 pathways in articular chondrocytes under hydrodynamic stimuli partially via Smad7. Collectively, transient exposure to growth factors is likely to maintain chondrocyte homeostasis, and thus promotes their anabolic activities under hydrodynamic stimuli. The present work suggests that robust hydrodynamically engineered neocartilage with a reduced fibrotic response and enhanced tissue homogeneity can be achieved through optimization of growth factor supplementation protocols and potentially through manipulation of intracellular signals such as Smad.

show abstract

“…For example, TGF-β1 mRNA levels are increased in human AD brains (20), which may be due to local tissue injury or reflect an attempt to compensate for the reduction in TβRII expression. Alternatively, excess ligand can reduce TβRII levels (37). Interestingly, levels of the neurotrophin receptors TRKA and TRKB are also decreased in AD, specifically in neurons affected by the disease (4, 38, 39).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology

Tesseur¹,

Zou²,

Esposito³

et al. 2006

J. Clin. Invest.

316

242

View full text Add to dashboard Cite

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the β-amyloid peptide (Aβ), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-β type II receptor (TβRII) is mainly expressed by neurons, and that TβRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-β signaling in mice resulted in age-dependent neurodegeneration and promoted Aβ accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-β signaling caused neuronal degeneration and resulted in increased levels of secreted Aβ and β-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-β signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-β signaling may thus reduce neurodegeneration and be beneficial in AD. IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease that leads to loss of cognitive function in a large number of elderly people. The human AD brain is characterized by the accumulation of β-amyloid peptide (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles. In addition, there is degeneration of synapses and dendrites and a progressive loss of neurons involved in memory processes (1). The cause of this degeneration in AD remains unknown, and no effective treatments are available.Survival of neurons is dependent on extracellular signals from neurotrophic factors and related factors with trophic activity (reviewed in ref.2). Levels of the neurotrophin nerve growth factor (NGF) and its receptor, tropomyosin receptor kinase A (TRKA), as well as levels of brain-derived neurotrophic factor (BDNF) and its receptor, TRKB, are lower in human AD brains than in nondemented controls (2-5). It was therefore proposed that a deficiency in neurotrophic factor signaling would promote neurodegeneration and cognitive dysfunction in AD, but this hypothesis has not been tested using specific genetic inhibition of neurotrophic factor signaling in a mouse model for AD (reviewed in refs. 2, 6).

show abstract

Ligand-induced downregulation of receptors for TGF-beta in human osteoblast-like cells from adult donors

Cited by 28 publications

References 30 publications

Increased Cell Surface Expression of Receptors for Transforming Growth Factor-β on Osteoblasts from Patients with Osteogenesis imperfecta

Increased Cell Surface Expression of Receptors for Transforming Growth Factor-β on Osteoblasts from Patients with Osteogenesis imperfecta

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology

Contact Info

Product

Resources

About