MicroRNA-186 improves fracture healing through activating the bone morphogenetic protein signalling pathway by inhibiting SMAD6 in a mouse model of femoral fracture

Objectives MicroRNAs (miRNAs) have been reported as key regulators of bone formation, signalling, and repair. Fracture healing is a proliferative physiological process where the body facilitates the repair of a bone fracture. The aim of our study was to explore the effects of microRNA-186 (miR-186) on fracture healing through the bone morphogenetic protein (BMP) signalling pathway by binding to Smad family member 6 (SMAD6) in a mouse model of femoral fracture. Methods Microarray analysis was adopted to identify the regulatory miR of SMAD6. 3D micro-CT was performed to assess the bone volume (BV), bone volume fraction (BVF, BV/TV), and bone mineral density (BMD), followed by a biomechanical test for maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. The positive expression of SMAD6 in fracture tissues was measured. Moreover, the miR-186 level, messenger RNA (mRNA) level, and protein levels of SMAD6, BMP-2, and BMP-7 were examined. Results MicroRNA-186 was predicted to regulate SMAD6. Furthermore, SMAD6 was verified as a target gene of miR-186. Overexpressed miR-186 and SMAD6 silencing resulted in increased callus formation, BMD and BV/TV, as well as maximum load, maximum radial degrees, elastic radial degrees, and rigidity of the femur. In addition, the mRNA and protein levels of SMAD6 were decreased, while BMP-2 and BMP-7 levels were elevated in response to upregulated miR-186 and SMAD6 silencing. Conclusion In conclusion, the study indicated that miR-186 could activate the BMP signalling pathway to promote fracture healing by inhibiting SMAD6 in a mouse model of femoral fracture. Cite this article: Bone Joint Res 2019;8:550–562.

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Circulating bone morphogenetic protein levels and delayed fracture healing

International Orthopaedics ◽

10.1007/s00264-012-1750-z ◽

2012 ◽

Vol 37 (3) ◽

pp. 523-527 ◽

Cited By ~ 31

Author(s):

Laurens J. van Baardewijk ◽

Jacob van der Ende ◽

Suzanne Lissenberg-Thunnissen ◽

Loes M. Romijn ◽

Lukas J. A. C. Hawinkels ◽

...

Keyword(s):

Fracture Healing ◽

Bone Morphogenetic Protein ◽

Delayed Fracture ◽

Protein Levels ◽

Morphogenetic Protein ◽

Delayed Fracture Healing

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Molecular Enhancement of Fracture Healing - Is there a Role for Bone Morphogenetic Protein-2, Parathyroid Hormone, Statins, or Sclerostin-Antibodies?

Injury ◽

10.1016/j.injury.2021.04.068 ◽

2021 ◽

Author(s):

Leopold Henssler ◽

Maximilian Kerschbaum ◽

Moldakulov Z. Mukashevich ◽

Markus Rupp ◽

Volker Alt

Keyword(s):

Parathyroid Hormone ◽

Fracture Healing ◽

Bone Morphogenetic Protein ◽

Bone Morphogenetic Protein 2 ◽

Morphogenetic Protein

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The Effect of Methylprednisolone on Porcine Bone Morphogenetic Protein in Fracture Healing

Clinical Orthopaedics and Related Research ◽

10.1097/00003086-199307000-00048 ◽

1993 ◽

Vol 292 ◽

pp. 366-375 ◽

Cited By ~ 5

Author(s):

KITTI JIRARATTANAPHOCHAI ◽

TAN SER KIAT ◽

DAVID CWA ◽

SONG IN CHIN

Keyword(s):

Fracture Healing ◽

Bone Morphogenetic Protein ◽

Morphogenetic Protein

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PHYSICAL EXERCISE IN THE PROMOTION OF GENE THERAPY AUXILIARY EFFECT

Revista Brasileira de Medicina do Esporte ◽

10.1590/1517-8692202127082021_0360 ◽

2021 ◽

Vol 27 (8) ◽

pp. 779-782

Author(s):

Wei Shen ◽

Xiaojun Liang

Keyword(s):

Gene Therapy ◽

Growth Factors ◽

Growth Factor ◽

Physical Exercise ◽

Fracture Healing ◽

Bone Morphogenetic Protein ◽

Bone Growth ◽

Transforming Growth Factor ◽

Transforming Growth Factors ◽

Morphogenetic Protein

ABSTRACT Introduction: In recent years, genetic engineering has made outstanding contributions to sports, and it has played a huge role in promoting the development of sports-related fields. Objective: We analyze the tissue source of bone growth and healing by studying the role of bone morphogenetic protein and transforming growth factors in fracture injuries caused by sports. Methods: We established a human fracture model to express the shape and content of bone morphogenetic protein and transforming growth factor during fracture healing. Results: In the fracture healing stage caused by different sports, the expression levels of the two genes are different. Bone morphogenetic protein has a high content in the osteogenesis stage of the membrane, while transforming growth factor is high in the cartilage ossification stage. Conclusion: Gene therapy for fractures caused by physical exercise has certain advantages. Osteoblasts and chondrocytes are involved in the synthesis of transforming growth factors. Level of evidence II; Therapeutic studies - investigation of treatment results.

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Single nucleotide polymorphism of bone morphogenetic protein 4 gene: A risk factor of non-syndromic cleft lip with or without palate

Indian Journal of Plastic Surgery ◽

10.4103/0970-0358.163053 ◽

2015 ◽

Vol 48 (02) ◽

pp. 159-164 ◽

Cited By ~ 5

Author(s):

Sathyaprasad Savitha ◽

S. M. Sharma ◽

Shetty Veena ◽

R. Rekha

Keyword(s):

Bone Morphogenetic Protein ◽

Cleft Lip ◽

Paediatric Population ◽

Single Nucleotide ◽

Morphogenetic Protein ◽

Increased Risk ◽

Polymerase Chain ◽

Bmp Signalling ◽

Control Study

ABSTRACT Background: The bone morphogenetic protein (BMP) signalling pathway is crucial in a number of developmental processes and is critical in the formation of variety of craniofacial elements including cranial neural crest, facial primordium, tooth, lip and palate. It is an important mediator in regulation of lip and palate fusion, cartilage and bone formation. Aim: To study the role of mutation of BMP4 genes in the aetiology of non-syndromic cleft lip with or without palate (NSCL ± P) and identify it directly from human analyses. Materials and Methods: A case-control study was done to evaluate whether BMP4T538C polymorphism, resulting in an amino acid change of Val=Ala (V152A) in the polypeptide, is associated with NSCL ± P in an Indian paediatric population. Genotypes of 100 patients with NSCL ± P and 100 controls (in whom absence of CL ± P was confirmed in three generations) were detected using a polymerase chain reaction-restriction fragment length polymorphism strategy. Logistic regression was performed to evaluate allele and genotype association with NSCLP. Results: Results showed significant association between homozygous CC genotype with CL ± P (odds ratio [OR]-5.59 and 95% confidence interval [CI] = 2.85-10.99). The 538C allele carriers showed an increased risk of NSCL ± P as compared with 538 T allele (OR - 4.2% CI = 2.75-6.41). Conclusion: This study suggests an association between SNP of BMP4 gene among carriers of the C allele and increased risk for NSCLP in an Indian Population. Further studies on this aspect can scale large heights in preventive strategies for NSCLP that may soon become a reality.

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P4461Cardiac-selective bone morphogenetic protein 7 (BMP7) gene therapy to target cardiac fibrosis in a mouse model of diabetic cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehx504.p4461 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

M. Tate ◽

O. Oseghale ◽

M.J. De Blasio ◽

D. Prakoso ◽

H. Qian ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Bone Morphogenetic Protein ◽

Diabetic Cardiomyopathy ◽

Cardiac Fibrosis ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein

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Blockage of bone morphogenetic protein signalling counteracts hypertrophy in a human osteoarthritic micro-cartilage model

Journal of Cell Science ◽

10.1242/jcs.249094 ◽

2020 ◽

Vol 133 (23) ◽

pp. jcs249094 ◽

Cited By ~ 1

Author(s):

Shikha Chawla ◽

Majoska H. M. Berkelaar ◽

Boris Dasen ◽

Christine Halleux ◽

Sabine Guth-Gundel ◽

...

Keyword(s):

Bone Morphogenetic Protein ◽

Selective Inhibition ◽

Type I ◽

Mesenchymal Progenitors ◽

Morphogenetic Protein ◽

Cartilage Extracellular Matrix ◽

Embryonic Cartilage ◽

Oa Chondrocytes ◽

Bmp Signalling

ABSTRACTBone morphogenetic protein (BMP) signalling plays a significant role during embryonic cartilage development and has been associated with osteoarthritis (OA) pathogenesis, being in both cases involved in triggering hypertrophy. Inspired by recent findings that BMP inhibition counteracts hypertrophic differentiation of human mesenchymal progenitors, we hypothesized that selective inhibition of BMP signalling would mitigate hypertrophic features in OA cartilage. First, a 3D in vitro OA micro-cartilage model was established using minimally expanded OA chondrocytes that was reproducibly able to capture OA-like hypertrophic features. BMP signalling was then restricted by means of two BMP receptor type I inhibitors, resulting in reduction of OA hypertrophic traits while maintaining synthesis of cartilage extracellular matrix. Our findings open potential pharmacological strategies for counteracting cartilage hypertrophy in OA and support the broader perspective that key signalling pathways known from developmental processes can guide the understanding, and possibly the mitigation, of adult pathological features.

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