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10 Q&As
Facts about Growth/differentiation factor 5.
Primarily, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complicated phosphorylation and then SMAD protein signaling transduction (PubMed:24098149, PubMed:21976273, PubMed:15530414, PubMed:25092592). Second, negatively regulates chondrogenic differentiation through its interaction with NOG (PubMed:21976273).
Human | |
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Gene Name: | GDF5 |
Uniprot: | P43026 |
Entrez: | 8200 |
Belongs to: |
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TGF-beta family |
BMP14; BMP-14; Cartilage-derived morphogenetic protein 1; cartilage-derived morphogenetic protein-1; CDMP-1; CDMP1LAP4; GDF5; GDF-5; growth differentiation factor 5; growth/differentiation factor 5; OS5; radotermin; SYNS2
Mass (kDA):
55.411 kDA
Human | |
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Location: | 20q11.22 |
Sequence: | 20; NC_000020.11 (35433347..35454749, complement) |
Predominantly expressed in long bones during embryonic development. Expressed in monocytes (at protein level).
Secreted. Cell membrane.
GDF5 is a 501-amino acids protein that interacts and is essential for cartilage biology. In this article, we'll discuss what GDF5 does and how it's used in biomedical applications. We'll also be discussing the possible uses of GDF5 as a marker. We'll also talk about BMPR1B a gene that's largely involved in the repair of damaged cartilage.
GDF5, a 501-amino acid protein, is an important regulator for embryonic joint and skeletal development. GDF5 mutations have been linked to several types of skeletal disorders, including Du Pan syndrome (multiple synostoses syndrome type 1) and proximal lymphalangism (proximal). GDF5 is a 501 amino-acid protein with many functions.
GDF5 mutations cause premature vertebral disease. Numerous studies have identified a "truncation" mutation at c.1461. This mutation truncates the protein by 15 amino acids, deletes two cysteine residues, and causes a premature stop codon. Mutations in GDF5 can be the cause of spondylolysis. This rare disorder can affect children as well as adults.
Mutations in GDF5 lead to abnormal function. This protein is a member of the TGF-beta superfamily. It contains a polybasic proteolytic processing area, which is essential to regulate cell growth and differentiation. Acromegaly, Brochydactyly, and Chondrodysplasia are all associated with mutations in this gene.
GDF5 recombinant genes share at least 60% identity in common with human GDF-5. These proteins also have high amino acids identity, which means that they must share at least 60% identity (or more) with human GDF-5’s cystine-knotdomain. Although this may seem too high for some applications it is sufficient to ensure GDF-5 function in cells.
Recently, the 501 amino acids GDF5 were cloned from cDNA of human embryos. They were then screened in fibroblasts. The protein contains a possible polybasic processing spot and a N–glycosylation location near its C end. The mature protein has a calculated amino acid count of 120 and a molecular weight of 13.6 kD. GDF5's cDNA sequence is 91% identical in mouse versus human. The mature proteins differ by an amino acid. All 10 cysteines are conserved.
Many mice carrying the mutation Gdf5L367R exhibit abnormal limb formation, including phalange fused. GDF5SYM1 mice exhibit abnormal joint formation. A mutation in GDF5L367R results in NOG, a protein that is affected by GDF5. It also inhibits the production of GDF5.
hGDF-5 mutants exhibit greater biological activity than the wild-type protein. The ATDC-5 and MCT1/26 cells also show greater activity for the hGDF-5 mutants. These results suggest GDF5 is involved the regulation of a variety immune responses. This discovery paves the way for improved treatment of a range of diseases. The GDF5 gene is essential for healthy immune function.
Although BMPR1 is involved with bone formation, GDF5 and BMPR1 are not yet fully understood. This protein's function is still unclear. In this study, we have investigated whether GDF5 can activate the ALP gene in C2C12 cells. GDF5 treatment caused an increase in ALP activity in C2C12-cells despite them not being high in Bmpr1b. It is possible that these cells have a high BMP receptor capacity and GDF5 cannot access it.
This study indicates that the BMPs BMPR1A and BMPR1B may play a dual role in joint morphogenesis. BMPR1A expression is found in mesenchymal cell during joint morphogenesis. BMPR1B expression is found in cartilage. Although we don't know the exact function of these receptors, it is known that they are involved in bone and cartilage formation. In this study, we generated GDF5 mutants that show reduced affinity for BMPR1A and BMPR1B and tested their chondrogenic activity in chondrocytes. Compared to wild-type GDF5 and BMPR1A, the mutants with decreased affinity for BMPR1A were unable to induce chondrogenic activity. Consequently, the function of these
We have shown that GDF5 can stimulate the expression of several markers, including Acan and Col2a1, but not Col10a1 or SOX9. R399E has no effect on GDF5's chondrogenic ability. R399E, W417F and BMP2 have little or no effect on hypertrophy markers. GDF5 as well as BMP2 had opposite effects on hypertrophy markers, according to the study.
Mutations in BMPR1B cause phenotypic aberrations in bone and are associated with a variety of disorders. Brachydactyly A2 is the most common. It results in aberrant signals in other tissues, organs, and cells. This mutation is responsible the majority of observed phenotypic anomalies. It is also associated with childhood pulmonary arterial hightension.
Mutants of GDF5 showed reduced affinities for BMPR1A and BMPR1B. To compare the potency and selectivity of the different compounds, Kd values were determined. The R399E mutant had the lowest affinity for BMPR1A/BMPR2 and was more effective at inducing dimerization of BMPR1A/BMPR2.
A mouse model of TBI demonstrated that GDF-5 supplementation to the hippocampus boosted neurogenesis and enhanced functional recovery. These findings suggest that GDF-5 could be a therapeutic agent for TBI. The exact mechanisms behind these effects are still unknown. To determine how this hormone interacts and affects mDA neurons, it is important to understand how BMPR1B works.
GDF5 found in articular cartilage is a sign of OA. We examined the effect GDF5 had on BMSC migration in this study. In the scratch assay we found that BMSCs embedded with Ad-GDF5 in a composite watergel were more migratory that control BMSCs. We also examined the migration by staining BMSCs with calcein color.
GDF5 gene level was confirmed in hip cartilage samples collected from patients with DDH. At four weeks, GDF5 expression was significantly higher in hip cartilage from DDH-affected rats than at twelve weeks. However, it decreased dramatically at 12 week. GDF5 expression was associated to severe arthritic changes in DDH patients. There was also a significant allelic variation. These results support our hypothesis, that GDF5 can be used to identify DDH adipose.
The GDF5 cartilage marker can also be used in a 3D bioprinted cartilage structure. We were able create a cartilage scaffold that is structurally sound, and which can be used to promote MSC differentiation by sequentially coprinting a BMSC laden hydrogel with a synthesized polymer. These cartilage scaffolds are highly mechanically and architecturally sound, which allows for the implantation bioprinted spheres.
GDF5 mutations can cause defects in certain joints. Ablation of Bmpr-1b can cause defects in the development of limb joints in mice. GDF5 also has been shown to play morphogenetic functions in certain joints. This gene is crucial for joint development and can be used to identify limb defects in humans. GDF5 is complex genetically. We may need to develop genetic tests to identify the genes that cause the defects.
The new scaffold can be used for cartilage repair in rabbit knees. BMSCs were extracted from rabbit BMSCs, and encapsulated in GDF5-conjugated Hydrogel. In order to create a favorable microenvironment for cell adhesion/proliferation, BMSCs-laden watergel was made from gelatines and fibrinogen. Glycerol, HA, and glycerol were also employed to improve cell dispensing uniformity and prevent nozzle obstruction at low temperatures.
GDF5 was subject to single-nucleotide mutations. In vitro, the mutant GDF5 protein showed an inactive state and a dominant positive effect, which inhibited expression of related BMPs. These mutations are likely caused by heterodimers. If we can find a gene that controls this defect, we may be able to overcome it.
PMID: 7980526 by Hoetten G., et al. Cloning and expression of recombinant human growth/differentiation factor 5.
PMID: 7961761 by Chang S., et al. Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development.
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