A Single Residue of GDF-5 Defines Binding Specificity to BMP Receptor IB

Nickel, J. Curtis; Kotzsch, Alexander; Sebald, Walter; Mueller, Thomas D.

doi:10.1016/j.jmb.2005.04.015

Cited by 138 publications

(156 citation statements)

References 49 publications

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“…Our choice of genes was governed by our previous finding of effects of exogenous GDFs and the fact that follistatin is expressed around the forming tendon in chicken embryos, where exogenous follistatin inhibits tendon formation [4]. BMPR1b was chosen because it is known to interact with GDF-5, which does not bind to BMPR1a [13].…”

Section: Discussionmentioning

confidence: 99%

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

Eliasson

Fahlgren

Aspenberg

2008

Clinical Orthopaedics &Amp; Related Research

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Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3 = 4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP-2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all time points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

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Section: Discussionmentioning

confidence: 99%

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

Eliasson

Fahlgren

Aspenberg

2008

Clinical Orthopaedics &Amp; Related Research

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“…SYM1, SYNS1, and SYNS2 syndromes are characterized by multiple joint fusions that are restricted to proximal interphalangeal joints of the hands and feet and carpal and tarsal bones; SYNS1 and SYNS2 patients additionally display multiple joint fusions in vertebrae and the hip (da-Silva et al 1984;Gaal et al 1987;Gong et al 1999;Takahashi et al 2001;Mangino et al 2002). SYM1 is caused by gain-of-function mutations in GDF5 that strongly increase ligand affinity for the BMPRIA receptor and result in loss of binding specificity for BMPRIB (Nickel et al 2005;Seemann et al 2005). Increased BMP signaling activity also follows from GDF5 mutations that render GDF-5 resistant to noggin and cause SYNS2 (Schwaerzer et al 2012;Degenkolbe et al 2013).…”

Section: Digit Malformations Caused By Disruption Of Tgf-b and Bmp Simentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…3,27 We tested whether BMPR1B C53R can mediate GDF5-dependent signaling with a BMP responsive luciferase (BRE) reporter assay. NIH/ 3T3 cells were transiently co-transfected with a BRE luciferase reporter and expression constructs of either BMPR1B wt , BMPR1B C53R , or BMPR1B dLBD .…”

Section: Gdf5-dependent Receptor Activation Is Lost In Bmpr1b C53rmentioning

confidence: 99%

“…GDF5 binds extracellular to transmembrane serine threonine kinases such as BMPR1A and BMPR1B, with a preference for BMPR1B. 3 All reported mutations in GDF5 associated with ACD are caused by a homozygous functional loss of GDF5, which is caused by either deletions, duplications, or insertions leading to a premature translational stop or caused by point mutations targeting the cleavage site or the mature domain of GDF5, thereby compromising its regular function. [4][5][6][7][8][9][10][11][12][13] Interestingly, one individual with a homozygous mutation in BMPR1B has been reported presenting with a subtype of ACD with additional genital anomalies, 14 implicating that mutations in the ligand and its receptor can cause similar phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

et al. 2013

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Acromesomelic chondrodysplasias (ACDs) are characterized by disproportionate shortening of the appendicular skeleton, predominantly affecting the middle (forearms and forelegs) and distal segments (hands and feet). Here, we present two consanguineous families with missense (c.157T4C, p.(C53R)) or nonsense (c.657G4A, p.(W219*)) mutations in BMPR1B. Homozygous affected individuals show clinical and radiographic findings consistent with ACD-type Grebe. Functional analysis of the missense mutation C53R revealed that the mutated receptor was partially located at the cell membrane. In contrast to the wild-type receptor, C53R mutation hindered the activation of the receptor by its ligand GDF5, as shown by reporter gene assay. Further, overexpression of the C53R mutation in an in vitro chondrogenesis assay showed no effect on cell differentiation, indicating a loss of function. The nonsense mutation (c.657G4A, p.(W219*)) introduces a premature stop codon, which is predicted to be subject to nonsense-mediated mRNA decay, causing reduced protein translation of the mutant allele. A lossof-function effect of both mutations causing recessive ACD-type Grebe is further supported by the mild brachydactyly or even non-penetrance of these mutations observed in the heterozygous parents. In contrast, dominant-negative BMPR1B mutations described previously are associated with autosomal-dominant brachydactyly-type A2.

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A Single Residue of GDF-5 Defines Binding Specificity to BMP Receptor IB

Cited by 138 publications

References 49 publications

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

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