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==R399E, a mutated form of GDF5, for disease modification of osteoarthritis==
<StructureSection load='7zjf' size='340' side='right'caption='[[7zjf]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7zjf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZJF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZJF FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7zjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zjf OCA], [https://pdbe.org/7zjf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zjf RCSB], [https://www.ebi.ac.uk/pdbsum/7zjf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zjf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Grebe type (AMDG) [MIM:[https://omim.org/entry/200700 200700]. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.<ref>PMID:9288098</ref>   Defects in GDF5 are the cause of acromesomelic chondrodysplasia Hunter-Thompson type (AMDH) [MIM:[https://omim.org/entry/201250 201250]. AMDH is an autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.  Defects in GDF5 are the cause of brachydactyly type C (BDC) [MIM:[https://omim.org/entry/113100 113100]. BDC is an autosomal dominant disorder characterized by an abnormal shortness of the fingers and toes. Note=Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).<ref>PMID:22828468</ref> <ref>PMID:14735582</ref>   Defects in GDF5 are the cause of Du Pan syndrome (DPS) [MIM:[https://omim.org/entry/228900 228900]; also known as fibular hypoplasia and complex brachydactyly. Du Pan syndrome is a rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.<ref>PMID:12121354</ref> <ref>PMID:16222676</ref> <ref>PMID:18629880</ref>   Defects in GDF5 are a cause of symphalangism proximal syndrome (SYM1) [MIM:[https://omim.org/entry/185800 185800]. SYM1 is characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.<ref>PMID:16127465</ref> <ref>PMID:16892395</ref> <ref>PMID:18283415</ref>   Defects in GDF5 are the cause of multiple synostoses syndrome type 2 (SYNS2) [MIM:[https://omim.org/entry/610017 610017]. Multiple synostoses syndrome is an autosomal dominant condition characterized by progressive joint fusions of the fingers, wrists, ankles and cervical spine, characteristic facies and progressive conductive deafness.[:]<ref>PMID:16532400</ref>   Defects in GDF5 are a cause of brachydactyly type A2 (BDA2) [MIM:[https://omim.org/entry/112600 112600]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:16127465</ref> <ref>PMID:18203755</ref>   Genetic variations in GDF5 are associated with susceptibility to osteoarthritis type 5 (OS5) [MIM:[https://omim.org/entry/612400 612400]. Osteoarthritis is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement.  Defects in GDF5 may be a cause of brachydactyly type A1 (BDA1) [MIM:[https://omim.org/entry/112500 112500]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.<ref>PMID:20683927</ref> 
== Function ==
[https://www.uniprot.org/uniprot/GDF5_HUMAN GDF5_HUMAN] Could be involved in bone and cartilage formation. Chondrogenic signaling is mediated by the high-affinity receptor BMPR1B.<ref>PMID:15530414</ref> <ref>PMID:19229295</ref> 
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== Publication Abstract from PubMed ==
OBJECTIVE: To preclinically characterize a mutant form of growth and differentiation factor 5 (GDF5, R399E) with reduced osteogenic properties, as a potential disease-modifying osteoarthritis (OA) drug. METHODS: Cartilage, synovium and meniscus from patients with OA were used to evaluate anabolic and anti-inflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intra-articular (IA) R399E doses were administered bi-weekly 6 times and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in-life, and OA was assessed after 13 weeks. RESULTS: Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in chondrocyte 3D cultures. R399E also inhibited the release of interleukin (IL)-1beta, IL-6 and prostaglandin E2 (PGE2) from cartilage with synovium, meniscal cell and synoviocyte cultures. In rabbits, mean difference (95% confidence interval (CI)) in weight bearing for R399E vs. vehicle was -5.8 (-9.54, -2.15), -7.2 (-10.93, -3.54) and -7.7 (-11.49, -3.84) for 0.6, 6 and 60 mug doses 6 hours after first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6 mug dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA. CONCLUSION: R399E influences several pathological processes contributing to OA, highlighting its potential as a disease-modifying therapy.

R399E, a mutated form of Growth and Differentiation Factor 5, for disease modification of osteoarthritis.,Gigout A, Werkmann D, Menges S, Brenneis C, Henson F, Cowan KJ, Musil D, Thudium CS, Guhring H, Michaelis M, Kleinschmidt-Doerr K Arthritis Rheumatol. 2022 Sep 2. doi: 10.1002/art.42343. PMID:36054172<ref>PMID:36054172</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7zjf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brenneis C]]
[[Category: Cowan KJ]]
[[Category: Gigout A]]
[[Category: Guehring H]]
[[Category: Henson F]]
[[Category: Kleinschmidt-Doerr K]]
[[Category: Menges S]]
[[Category: Michaelis M]]
[[Category: Musil D]]
[[Category: Thudium C]]
[[Category: Wekmann D]]