Growth differentiation factor 5 in cartilage and osteoarthritis: A possible therapeutic candidate

Background: Bone Morphogenetic Proteins (BMPs) regulate diverse cellular functions during foetal development and postnatal life. Growth Differentiation Factor 5 (GDF5 a.k.a. BMP-14) is a BMP, which is expressed in a variety of tissues including heart. We previously showed that cardiac GDF5 mRNA levels are elevated after experimental myocardial infarction (MI) caused by permanent left anterior descending coronary artery (LAD) ligation. However, the significance of this finding was not known. Methods & Results: GDF5 knock-out (KO; n = 18 for MI) and wild-type (WT; n = 18 for MI) littermate controls were subjected to chronic LAD ligation in order to investigate the consequences resulting from the loss of GDF5 signalling following MI. At 28 days post-LAD ligation or sham (n = 12 for KO; n = 10 for WT), invasive hemodynamic parameters of cardiac function were examined just prior to sacrifice. Histopathology was assessed by morphometric analyses of perfusion fixed hearts and subsequent immunostaining. At 28 days post-MI, GDF5-KO mice exhibited decreased left ventricular systolic pressure and peak positive- and negative- dP/dt , and increased heart rate as compared to WT littermates ( P < 0.005 for each parameters). GDF5-KO mice also exhibited a significant increase in the area, length and transmural expansion of the infarct, scar thinning and cardiac dilatation ( P < 0.05 for each parameter). In addition, GDF5-KO mice displayed significantly fewer myocardial vessels in the infarct and peri-infarct regions as compared to WT littermates ( P < 0.05) . To explore mechanisms underlying this phenotype, we assessed gene expression levels of relevant potential downstream targets of GDF5. At 7d post-MI, quantitative RT-PCR revealed a significant reduction (35%) in VEGF mRNA levels in hearts of KO (n = 6) as compared to WT mice (n = 5, P = 0.033). Summary & Conclusion: These data suggest that increased GDF5 expression observed in hearts after MI plays an important role in cardiac remodelling. Absence of GDF5 expression in KO mice confers detrimental effects on healing and repair of myocardial and vascular tissues after MI. Regulated levels of GDF5, a BMP family member, play an important role in the repair process following cardiac injury.

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Growth differentiation factor 5 modulation of chondrogenesis of self-assembled constructs involves gap junction-mediated intercellular communication

Development Growth & Differentiation ◽

10.1111/dgd.12009 ◽

2012 ◽

Vol 54 (9) ◽

pp. 809-817 ◽

Cited By ~ 10

Author(s):

Zhibo Sun ◽

Yukun Zhang ◽

Shuhua Yang ◽

Jie Jia ◽

Shunan Ye ◽

...

Keyword(s):

Gap Junction ◽

Intercellular Communication ◽

Differentiation Factor ◽

Self Assembled ◽

Growth Differentiation Factor 5

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Dose-Response Tendon-Specific Markers Induction by Growth Differentiation Factor-5 in Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21165905 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5905

Author(s):

Maria Camilla Ciardulli ◽

Luigi Marino ◽

Erwin Pavel Lamparelli ◽

Maurizio Guida ◽

Nicholas Robert Forsyth ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cell Types ◽

Human Bone ◽

Human Bone Marrow ◽

Differentiation Factor ◽

Anti Inflammatory ◽

Growth Differentiation Factor 5

Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton’s Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 (hGDF-5) we supplemented each at doses of 1, 10, and 100 ng/mL of hGDF-5 and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated the expression of collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis-A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed up-regulation of SCX-A (1.7-fold) at Day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX-A (3.8-fold) and TNC (2.3-fold) after three days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular-shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this, we explored the expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines up-regulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold), but a greater up-regulation of IL-10 (2.5-fold). Type 1 collagen and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification with a length/width ratio increase, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue-engineering protocols.

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Association between growth differentiation factor 5 rs143383 genetic polymorphism and the risk of knee osteoarthritis among Caucasian but not Asian: a meta-analysis

Arthritis Research & Therapy ◽

10.1186/s13075-020-02306-9 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Lei Peng ◽

Song Jin ◽

Jiping Lu ◽

Chao Ouyang ◽

Jiang Guo ◽

...

Keyword(s):

Genetic Polymorphism ◽

Knee Osteoarthritis ◽

Meta Analysis ◽

Recessive Model ◽

Cochrane Library ◽

China National Knowledge Infrastructure ◽

Differentiation Factor ◽

Model C ◽

Relationship Of ◽

Growth Differentiation Factor 5

Abstract Background A few months ago, the Bioscience Reports journal showed that growth differentiation factor 5 (GDF5) rs143383 genetic polymorphism increases the susceptibility of knee osteoarthritis (KOA), but previous studies’ results have debates about available data. Considering the availability of more recent data, we focus on clarifying the relationship of KOA and GDF5 rs143383 genetic polymorphism by a meta-analysis of case-control trial data. Methods The eligible studies from the time of database established to Oct. 2019 were collected from PubMed, Springer, Cochrane library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang library. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate the association between these polymorphisms and KOA risk. The meta-analysis was completed by STATA 18.0 software. Results A total of 196 studies were collected, 16 of them included in final meta-analysis (7997 cases and 12,684 controls). There was significant association between GDF5 rs143383 polymorphism and KOA in all genetic models (for Allele model (C versus T): OR = 0.84 (95% CI = 0.76–0.91); dominate model (CC+CT versus TT): OR = 0.80 (95% CI = 0.72–0.90); recessive model (CC versus CT+TT): OR = 0.79 (95% CI = 0.68–0.92); heterozygote model (CT versus CC+TT): OR = 0.89 (95% CI = 0.80–0.97); homozygous model (CC versus TT): OR = 0.71 (95% CI = 0.60–0.85)). In the subgroup analysis, we obtained the results that there is no significance among Asians. Conclusion GDF5 rs143383 genetic polymorphism increases the risk of KOA among Caucasians; CC genotype and C allele are protective factors for the susceptibility of KOA among Caucasians.

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