Association between fibroblast growth factor 21 and bone mineral density in adults

Hao, Ruo-Han; Gao, Jiyun; Li, Meng; Huang, Wei; Zhu, Dong-Li; Thynn, Hlaing Nwe; Dong, Shanshan; Guo, Yan

doi:10.1007/s12020-017-1507-y

Cited by 26 publications

(28 citation statements)

References 22 publications

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“…In agreement with our study, other investigators also reported lower BMD at the lumbar spine, femoral neck and hip during ageing in both men and women (Riggs et al., 2004; Warming, Hassager, & Christiansen, 2002). In healthy elderly males and females, aged ∼60 years, BMD at the lumbar spine was not associated with FGF21 concentrations after adjusting for sex and age (Hao et al., 2018), in agreement with our findings. However, in that study, BMD at the femoral neck was negatively associated with the FGF21 concentration, even after adjusting for age and sex.…”

Section: Discussionsupporting

confidence: 92%

“…Our study included participants with hypertension and type 2 diabetes that were well controlled with medication but were free from musculoskeletal diseases. This participant profile differed from earlier studies that were conducted on healthy participants without medications (Lee et al., 2013) or without chronic diseases (Hao et al., 2018) and women with fragility fractures (Hu et al., 2019). The lack of agreement in results could be attributable to differences in lifestyle or samples tested and the inclusion of both sexes in our study, which differed from earlier studies that included only younger (Lee et al., 2013) and older women (Choi et al., 2018; Hu et al., 2019).…”

Section: Discussionmentioning

confidence: 67%

“…Pharmacological administration of FGF21 in humans has adverse effects on bone turnover, such as increased concentrations of bone resorption markers and decreased concentrations of bone formation markers (Kim et al., 2017; Talukdar et al., 2016). A negative association between fasting plasma FGF21 concentration and BMD has also been found in elderly individuals aged ∼60 years old (Hao et al., 2018). These results suggest that FGF21 contributes to age‐related bone loss.…”

Section: Introductionmentioning

confidence: 94%

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Age‐related bone loss is associated with FGF21 but not IGFBP1 in healthy adults

Lee

Fam

Chia

et al. 2020

Experimental Physiology

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Bone fragility increases with age. The fibroblast growth factor 21 (FGF21)-insulin-like growth factor binding protein 1 (IGFBP1) axis regulates bone loss in animals. However, the role of FGF21 in mediating age-associated bone fragility in humans remains unknown. The purpose of this study was to explore the FGF21-regulatory axis in bone turnover and the age-related decline in bone mineral density (BMD). Twenty 'genetically linked' family (parent and child) pairs were recruited. Younger adults were 22-39 years old and older adults 60-71 years old. The BMD and serum concentrations of FGF21, IGFBP1, receptor activator of nuclear factor-B ligand (RANKL), tartrate-resistant acid phosphatase 5b (TRAP5b) and bone-specific alkaline phosphatase (BAP) were measured. Older adults had 10-18% lower BMD at the hip and spine (P < 0.008) and a twofold higher FGF21 concentration (P < 0.001). The IGFBP1 concentration was similar in younger and older adults (P = 0.961). The RANKL concentration was 44% lower (P = 0.006), whereas TRAP5b and BAP concentrations were 36 and 31% higher (P = 0.01 and P = 0.004), respectively, in older adults than in younger adults. Adjusting for sex did not affect these results. The FGF21 concentration was negatively correlated with BMD at the spine (r = −0.460, P = 0.003), but not with the IGFBP1 concentration (r = −0.144, P = 0.374).The IGFBP1 concentration was not correlated with BMD at the hip or spine (all P > 0.05).In humans, FGF21 might be involved in the age-associated decline in BMD, especially at the spine, through increased bone turnover. IGFBP1 is unlikely to be the downstream effector of FGF21 in driving the age-associated decline in BMD and in RANKL-associated osteoclast differentiation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Age‐related bone loss is associated with FGF21 but not IGFBP1 in healthy adults

Lee

Fam

Chia

et al. 2020

Experimental Physiology

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“…In other studies, increased bone resorption and decreased bone formation biomarkers were also observed in plasma samples from obese monkeys and humans administer a long-acting FGF-21 analogue. (24) Plasma FGF-21 concentrations were negatively correlated with BMD in the femoral neck in Han Chinese adult population, (50) in human immunodeficiency virus 1 (HIV-1)infected patients, (51) and in radial trabecular bone microarchitecture and strength in women with anorexia nervosa. (52) However, others did not detect bone loss in rhFGF-21-treated (53) or AAV8-hAAT-FGF-21 genetically engineered (54) high-fat dietinduced obesity mice, in high-fat-fed obese monkeys (55) and minipigs (56) ; and FGF-21 knockout mice did not show high bone mass phenotype.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Sun

Qian

et al. 2019

Journal of Bone and Mineral Research

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Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy seen in children. In addition to skeletal muscle, DMD also has a significant impact on bone. The pathogenesis of bone abnormalities in DMD is still unknown. Recently, we have identified a novel bone‐regulating cytokine, fibroblast growth factor‐21 (FGF‐21), which is dramatically upregulated in skeletal muscles from DMD animal models. We hypothesize that muscle‐derived FGF‐21 negatively affects bone homeostasis in DMD. Dystrophin/utrophin double‐knockout (dKO) mice were used in this study. We found that the levels of circulating FGF‐21 were significantly higher in dKO mice than in age‐matched WT controls. Further tests on FGF‐21 expressing tissues revealed that both FGF‐21 mRNA and protein expression were dramatically upregulated in dystrophic skeletal muscles, whereas FGF‐21 mRNA expression was downregulated in liver and white adipose tissue (WAT) compared to WT controls. Neutralization of circulating FGF‐21 by i.p. injection of anti‐FGF‐21 antibody significantly alleviated progressive bone loss in weight‐bearing (vertebra, femur, and tibia) and non–weight bearing bones (parietal bones) in dKO mice. We also found that FGF‐21 directly promoted RANKL‐induced osteoclastogenesis from bone marrow macrophages (BMMs), as well as promoted adipogenesis while concomitantly inhibiting osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). Furthermore, fibroblast growth factor receptors (FGFRs) and co‐receptor β‐klotho (KLB) were expressed in bone cells (BMM‐derived osteoclasts and BMMSCs) and bone tissues. KLB knockdown by small interfering RNAs (siRNAs) significantly inhibited the effects of FGF21 on osteoclast formation of BMMs and on adipogenic differentiation of BMMSCs, indicating that FGF‐21 may directly affect dystrophic bone via the FGFRs‐β‐klotho complex. In conclusion, this study shows that dystrophic skeletal muscles express and secrete significant levels of FGF‐21, which negatively regulates bone homeostasis and represents an important pathological factor for the development of bone abnormalities in DMD. The current study highlights the importance of muscle/bone cross‐talk via muscle‐derived factors (myokines) in the pathogenesis of bone abnormalities in DMD. © 2019 American Society for Bone and Mineral Research.

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“…Additionally, a member of the fibroblast growth factors (FGFs) family, FGF21, is an essential endocrine hormone that regulates glucose and lipid metabolism (6). FGF21 affects bone development; it is inversely associated with regional bone mass density (BMD) (7). However, few studies have evaluated the core genes involved in OP using a bioinformatics approach.…”

Section: Introductionmentioning

confidence: 99%

Identification of core genes and prediction of miRNAs associated with osteoporosis using a bioinformatics approach

Chai

Tan

et al. 2018

Oncol Lett

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Osteoporosis (OP) is an age-related disease, and osteoporotic fracture is one of the major causes of disability and mortality in elderly patients (>70 years old). As the pathogenesis and molecular mechanism of OP remain unclear, the identification of disease biomarkers is important for guiding research and providing therapeutic targets. In the present study, core genes and microRNAs (miRNAs) associated with OP were identified. Differentially expressed genes (DEGs) between human mesenchymal stem cell specimens from normal osseous tissues and OP tissues were detected using the GEO2R tool of the Gene Expression Omnibus database and Morpheus. Network topological parameters were determined using NetworkAnalyzer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery, and ClueGO. Cytoscape with the Search Tool for the Retrieval of Interacting Genes and Molecular Complex Detection plug-in was used to visualize protein-protein interactions (PPIs). Additionally, miRNA-gene regulatory modules were predicted using CyTargetLinker in order to guide future research. In total, 915 DEGs were identified, including 774 upregulated and 141 downregulated genes. Enriched GO terms and pathways were determined, including 'nervous system development', 'regulation of molecular function', 'glutamatergic synapse pathway' and 'pathways in cancer'. The node degrees of DEGs followed power-law distributions. A PPI network with 541 nodes and 1,431 edges was obtained. Overall, 3 important modules were identified from the PPI network. The following 10 genes were identified as core genes based on high degrees of connectivity: Albumin, PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2), DNA topoisomerase 2-α, kininogen 1 (KNG1), interleukin 2 (IL2), leucine-rich repeats and guanylate kinase domain containing, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG), leptin, transferrin and RNA polymerase II subunit A (POLR2A). Additionally, 15 miRNA-target interactions were obtained using CyTargetLinker. Overall, 7 miRNAs co-regulated IL2, 3 regulated PHLPP2, 3 regulated KNG1, 1 regulated PIK3CG and 1 modulated POLR2A. These results indicate potential biomarkers in the pathogenesis of OP and therapeutic targets.

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Association between fibroblast growth factor 21 and bone mineral density in adults

Abstract: Taking together from both physiological and genetic levels, we suggest that FGF21 is inversely associated with regional BMD. And we haven't observed sex-specific effect in this study.

Cited by 26 publications

References 22 publications

Age‐related bone loss is associated with FGF21 but not IGFBP1 in healthy adults

Age‐related bone loss is associated with FGF21 but not IGFBP1 in healthy adults

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Identification of core genes and prediction of miRNAs associated with osteoporosis using a bioinformatics approach

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