Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity

Brkljačić, Jelena; Pauk, Martina; Erjavec, Igor; Cipcic, Antonio; Grgurević, Lovorka; Zadro, Renata; Inman, Gareth J.; Vukičević, Slobodan

doi:10.1007/s00264-012-1714-3

Cited by 27 publications

(24 citation statements)

References 57 publications

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“…Have Distinct Sequences and Binding Properties -As indicated above, the N-terminal regions of mature BMP5, BMP6 and BMP7 upstream of the cysteine knot are much longer than those in BMP2 and BMP4 and are currently thought to contain a major HS binding domain (31)(32)(33). To ask what may lie behind such length difference, we aligned the N-terminal regions from each BMP protein and compared the putative HSbinding domains within them, using the first conserved cysteine as a reference mark (Fig.…”

Section: N-terminal Regionsmentioning

confidence: 99%

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Domains with highest heparan sulfate–binding affinity reside at opposite ends in BMP2/4 versus BMP5/6/7: Implications for function

Billings

Yang

Mundy

et al. 2018

Journal of Biological Chemistry

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Signaling proteins, including bone morphogenetic proteins (BMPs), specifically interact with heparan sulfate (HS). These interactions regulate protein distribution and function and are largely mediated by domains rich in basic amino acids. The N-terminal region of BMP2 and BMP4 contains one such domain with a typical Cardin-Weintraub (CW) motif, but it is unclear whether the same occurs in BMP5, BMP6 and BMP7 that constitute a separate evolutionary subgroup. Peptides spanning the N-terminal domain of BMP2/4 interacted with substrate-bound HS with nanomolar affinity, but peptides spanning BMP5/6/7 N-terminal domain did not. We reexamined the entire BMP5/6/7 sequences and identified a novel CW-like motif at their Cterminus. Peptides spanning this domain displayed high affinity HS binding, but corresponding BMP2/4 C-terminal peptides did not, likely because of acidic or non-charged residue substitutions. Peptides pre-assembled into NeutrAvidin tetramers displayed the same exact binding selectivity of respective monomers, but bound HS with greater affinity. Tests of possible peptide biological activities showed that the HS-binding N-terminal BMP2/4 and C-terminal BMP5/6/7 peptides stimulated chondrogenesis in vitro, potentially by freeing endogenous BMPs. Thus, HS interactions appear largely ascribable to domains at opposite ends of BMP2/4 versus BMP5/6/7, reiterating the evolutionary distance of these BMP subgroups and possible functional diversification.

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Section: N-terminal Regionsmentioning

confidence: 99%

“…First, their HS-binding domains have not been well defined compared to those of BMP2 and BMP4 (31)(32)(33). Based on sequence homologies, the 3 proteins are classified as a separate evolutionary subgroup distinct from the BMP2/BMP4 subgroup within the TGF- superfamily (34).…”

Section: Introductionmentioning

confidence: 99%

Domains with highest heparan sulfate–binding affinity reside at opposite ends in BMP2/4 versus BMP5/6/7: Implications for function

Billings

Yang

Mundy

et al. 2018

Journal of Biological Chemistry

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“…35 Heparin anticoagulant activity is a result of high-affinity binding to antithrombin 36 and is structurally similar to the heparan sulfates of proteoglycans present on various cell types, including hepatocytes. 37 Heparan sulfates of proteoglycans are involved in many functions 38 and are coreceptors for the activity of growth factors and cytokines.…”

Section: Introductionmentioning

confidence: 99%

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Poli

Asperti

Naggi

et al. 2014

Blood

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Key Points• Chemically modified nonanticoagulant heparins are strong inhibitors of hepcidin expression in normal and Bmp6 2/2 mice. • These heparins abolish hepcidin induction caused by LPS, a model of inflammation, and are candidates for treatment of inflammatory anemia.Hepcidin controls systemic iron availability, and its excess contributes to the anemia of chronic diseases, the most prevalent anemia in hospitalized patients. We previously reported that heparins are efficient hepcidin inhibitors both in vitro and in vivo, but their anticoagulant activity limits therapeutic use. We studied nonanticoagulant heparins produced by N-acetylation and oxidation/reduction (glycol-split) that lost antithrombinbinding affinity. Four nonanticoagulant heparins inhibited hepcidin expression in hepatic HepG2 cells and primary hepatocytes. The 2 most potent ones used in mice suppressed liver hepcidin expression and serum hepcidin in 6 hours, with a significant decrease of spleen iron. This occurred also in lipopolysaccharide (LPS)-treated animals that mimic inflammation, as well as after chronic 1-week treatments, without evident adverse effects on coagulation. Heparin injections increased iron mobilization and facilitated the recovery from the anemia induced by heat-killed Brucella abortus, a model of inflammatory anemia. The heparins were used also in Bmp6 2/2 mice. A single dose of heparin reduced the already low level of hepcidin of these mice and prevented its induction by LPS. These nonanticoagulant compounds impair bone morphogenetic protein /sons of mothers against decapentaplegic signaling with no evident adverse effect in vivo, even when administered chronically. They may offer a strategy for the treatment of diseases with high hepcidin levels. (Blood. 2014;123(10):1564-1573

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“…Recently, a research disclosed that exogenous heparin reduced the BMP6 osteogenic activity by using μCT analysis of femur in the mice with osteoporotic (Brkljacic et al, 2013). Both SNP1 and SNP3 had significant correlation with FP (p<0.05).…”

Section: Bmp6mentioning

confidence: 99%

Detection of SNPs in the BMP6 Gene and Their Association with Carcass and Bone Traits in Chicken

Cui

et al. 2017

Rev. Bras. Cienc. Avic.

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BMP6, a member of the subfamilies of the morphogenetic proteins (BMPs), plays a crucial role in osteogenic and chondrocyte differentiation in vitro and stimulates chondrogenesis, making chondrocytes differentiate on their terminal stage. The objective of this study is to explore the relationship between polymorphism of BMP6 gene and slaughter traits in chicken respectively. We screened the exonic and intronic regions of BMP6 gene by DNA pool construction and amplified DNA fragment by PCR, and finally, we got nine SNPs. Association analysis revealed that BMP6 had no significant association among all slaughter traits in Yellow bantam chicken. However, BMP6 had a significant difference with femur weight, tibia weight, femur length (p<0.05), and was extremely significant with tibia length (p<0.01) in Avian chicken. Moreover, femur perimeter also had significant correlation with BMP6 in Avian chicken. These results provide useful information for further investigation on the function of chicken BMP6 gene.

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Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity

Cited by 27 publications

References 57 publications

Domains with highest heparan sulfate–binding affinity reside at opposite ends in BMP2/4 versus BMP5/6/7: Implications for function

Domains with highest heparan sulfate–binding affinity reside at opposite ends in BMP2/4 versus BMP5/6/7: Implications for function

Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Detection of SNPs in the BMP6 Gene and Their Association with Carcass and Bone Traits in Chicken

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