Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway

Sharma, Garima; Sharma, Ashish Ranjan; Seo, Eun-Min; Nam, Ju-Suk

doi:10.1155/2015/847529

Cited by 15 publications

(17 citation statements)

References 86 publications

(85 reference statements)

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“…Wnt signaling pathway is one of the most important pathways in differentiation and proliferation of bone cells. Very recently, Sharma et al (2015) reviewed the role of polymorphism in Wnt signaling modulator, thus shedding light on the origin of various diseases, including osteoporosis, towards the identification of novel pathways for potential therapy. Within the components of WNT signaling, the gene coding for WNT16 , one of the 19 WNT ligands of the human genome, was found strongly associated with specific bone traits.…”

Section: Major Biological Pathways Involved In Osteogenesis Related Tmentioning

confidence: 99%

An insight into the paradigms of osteoporosis: From genetics to biomechanics

et al. 2019

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Considered as one of the major epidemics of the 21st century, osteoporosis affects approximately 200 million people globally, with significant worldwide impact on rates of morbidity and mortality and massive socioeconomic burdens. Mainly characterized by decreased bone mineral density (BMD) and increased risk of bone fragility/deterioration, this devastating silent epidemic typically has no symptoms until a fracture occurs. The multifactorial disease, osteoporosis is instigated by complex interactions between genetic, metabolic and environmental factors, with severe impact on the biomechanics of the musculoskeletal system. This article provides a review of the epidemiology, genetic and biomechanical aspects of primary osteoporosis. The review begins with a summary of the epidemiology and global prevalence of osteoporosis. Sections 1 and 2 discuss the genetic associations and molecular signaling pathways involved in normal and pathological osteogenesis while Section 3 explores the biomechanics of osteoporosis and its quantitative damaging effects on critical bone mechanical properties, and associated bone remodeling. Overall, this review summarizes the recent findings about osteoporosis and emphasizes the importance of an integrative holistic approach in investigating osteoporosis towards providing better informed, more effective preventive and treatment modalities. Importantly, this work also explores the limited available literature on the various aspects of osteoporosis in the United Arab Emirates (UAE), Gulf Cooperation Council (GCC), and Middle East despite its alarming prevalence in the region, and highlights the need for further research and studies taking into consideration the importance of the vitamin D receptor ( VDR ) gene influencing the development of osteoporosis.

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Section: Major Biological Pathways Involved In Osteogenesis Related Tmentioning

confidence: 99%

An insight into the paradigms of osteoporosis: From genetics to biomechanics

et al. 2019

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“…As regards the molecular mechanisms, the positive miR-483-3p regulation of Wnt1, β-catenin and cyclin d1 suggests that miR-483-3p may target Wnt signaling antagonist(s) to exert a promoting effect on Wnt signaling. The Wnt signaling pathway is regulated by two main classes of modulators, which are classified based on their crosstalk with Wnt signaling or its receptors (35). Secreted frizzled-related proteins (SFRPs) belong to the class that not only bind to Wnt protein, but also antagonize Wnt signaling (36).…”

Section: Discussionmentioning

confidence: 99%

miR‑483‑3p promotes the osteogenesis of human osteoblasts by�targeting Dikkopf 2 (DKK2) and the Wnt signaling pathway

et al. 2020

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Osteoporosis is a systemic metabolic bone disease during which bone mass decreases and bone quality is reduced. Maintaining the bone formation capacity of osteoblasts is crucial for the treatment of osteoporosis. In the present study, bioinformatics analysis was performed on online microarray expression profiles to identify miRNA(s) related to osteoblast proliferation and bone marrow-derived mesenchymal stem cell (BMSc) osteogenic differentiation. The specific effects of candidate miRNAs on cell proliferation, osteogenic differentiation and Wnt signaling-related factors were examined. As regards the downstream mechanisms, online tools were employed to predict the downstream targets of candidate miRNAs and the predicted miRNA-mRNA binding was verified. Finally, the dynamic effects of miRNAs and mRNAs were examined. The results revealed that miR-483-3p expression was decreased in bone tissue samples from patients with osteoporosis. In miR-483-3p-overexpressing human osteoblasts, cell viability, dNA synthesis capacity and osteogenesis were promoted, and the protein levels of Wnt1, β-catenin and cyclin d1 were increased. However, the protein receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio and cell apoptotic rate were decreased. The Wnt signaling, antagonist dikkopf 2 (dKK2), was targeted and negatively regulated by miR-483-3p. dKK2 knockdown exerted similar effects as miR-483-3p overexpression, while dKK2 overexpression inhibited cell viability, dNA synthesis capacity and osteogenesis. dKK2 overexpression also decreased the Wnt1, β-catenin, and cyclin d1 protein levels, whereas it promoted the the RANKL/OPG ratio and the apoptosis of human osteoblasts. dKK2 overexpression reversed the functions of miR-483-3p overexpression. On the whole, the findings of the present study demonstrate that the miR-483-3p/dKK2 axis modulates the bone formation process by affecting osteoblast proliferation, pre-osteoblast differentiation into mature osteoblasts and new bone matrix formation.

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“…Sclerostin has a negative effect on bone formation by inhibiting canonical Wnt signalling in osteoblasts and also stimulates osteoclastic bone resorption by increasing the RANKL/OPG ratio (via enhanced RANKL expression) (Appelman-Dijkstra and Papapoulos 2016 ). Despite this strong influence on bone metabolism, conflicting results regarding SOST variants and association with BMD have been reported in the literature (Sharma et al 2015 ). Additionally, serum sclerostin concentration has been positively correlated with lumbar spine, femoral neck and total hip BMD but no variants were associated with BMD or sclerostin concentration (He et al 2014 ).…”

Section: Genetic Association With Bmdmentioning

confidence: 99%

The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes

et al. 2018

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Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk and can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by diet, hormonal characteristics and physical activity. The interrelationships between such factors, and a strong genetic component, suggested to be around 50–85% at various anatomical sites, determine skeletal health throughout life. Genome-wide association studies and case–control designs have revealed many loci associated with variation in BMD. However, a number of the candidate genes identified at these loci have no known associated biological function or have yet to be replicated in subsequent investigations. Furthermore, few investigations have considered gene–environment interactions—in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential injury risk. Therefore, this review considers the importance of physical activity on BMD, genetic associations with BMD and how subsequent investigation requires consideration of the interaction between these determinants. Future research using well-defined independent cohorts such as elite athletes, who experience much greater mechanical stress than most, to study such phenotypes, can provide a greater understanding of these factors as well as the biological underpinnings of such a physiologically “extreme” population. Subsequently, modification of training, exercise or rehabilitation programmes based on genetic characteristics could have substantial implications in both the sporting and public health domains once the fundamental research has been conducted successfully.

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Genetic Polymorphism in Extracellular Regulators of Wnt Signaling Pathway

Cited by 15 publications

References 86 publications

An insight into the paradigms of osteoporosis: From genetics to biomechanics

An insight into the paradigms of osteoporosis: From genetics to biomechanics

miR‑483‑3p promotes the osteogenesis of human osteoblasts by�targeting Dikkopf 2 (DKK2) and the Wnt signaling pathway

The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes

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