Skeletal effects of growth hormone and insulin-like growth factor-I therapy

Lindsey, Richard C; Mohan, Subburaman

doi:10.1016/j.mce.2015.09.017

Cited by 38 publications

(24 citation statements)

References 249 publications

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“…Defective periosteal bone growth occurred in males and females and was therefore unlikely to be caused by sex hormones. IGF-1 signaling can affect bone width (Lindsey and Mohan, 2016), but Bmp2 Prx1-cKO mice expressed IGF-1 in bone (Figure 1—figure supplement 1a) and circulating IGF-1 was statistically unchanged in Bmp2 Prx1-cKO mice (Figure 1—figure supplement 1b). During ex vivo organ culture, WT and Bmp2 Prx1-cKO metatarsals were equal in length on day one and both grew in culture (Figure 1n).…”

Section: Resultsmentioning

confidence: 99%

Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche

Salazar

Capelo

Cantù

et al. 2019

eLife

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Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only Bmp2 in the Prx1-Cre lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of Sp7 via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of BMP2 and GRHL3 are associated with increased risk of fractures.

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Section: Resultsmentioning

confidence: 99%

Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche

Salazar

Capelo

Cantù

et al. 2019

eLife

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“…Clinical trials for several of the molecules mentioned above are currently undertaken. These include IGF-1, which has showed that it increased BMD and is reviewed by Lindsey RC et al [ 123 ]. Osteocalcin, irisin, myostatin could be also targets for future trials in order to become drugs for both osteoporosis and sarcopenia treatments (for detailed review on these, see [ 124 ]).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Muscle–Bone Crosstalk: Emerging Opportunities for Novel Therapeutic Approaches to Treat Musculoskeletal Pathologies

2017

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Osteoporosis and sarcopenia are age-related musculoskeletal pathologies that often develop in parallel. Osteoporosis is characterized by a reduced bone mass and an increased fracture risk. Sarcopenia describes muscle wasting with an increasing risk of injuries due to falls. The medical treatment of both diseases costs billions in health care per year. With the impact on public health and economy, and considering the increasing life expectancy of populations, more efficient treatment regimens are sought. The biomechanical interaction between both tissues with muscle acting on bone is well established. Recently, both tissues were also determined as secretory endocrine organs affecting the function of one another. New exciting discoveries on this front are made each year, with novel signaling molecules being discovered and potential controversies being described. While this review does not claim completeness, it will summarize the current knowledge on both the biomechanical and the biochemical link between muscle and bone. The review will highlight the known secreted molecules by both tissues affecting the other and finish with an outlook on novel therapeutics that could emerge from these discoveries.

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“… 23 The synthesis of IGF-1 by osteoblasts is under the control of growth hormones and a deficiency of the growth hormone (GH)/IGF axis contributes to the development of low bone mass. 24 Our meQTLs-based gene set enrichment analysis reported significant associations between this gene set and the femoral neck and lumbar spine BMD. We also identified significant associations between Reactome GH receptor signalling and BMD in both the femoral neck and the lumbar spine, suggesting that genetically controlled methylation of the GH/IGF axis may play a critical role in bone metabolism.…”

Section: Discussionmentioning

confidence: 78%

Integrative analysis of GWAS, eQTLs and meQTLs data suggests that multiple gene sets are associated with bone mineral density

Wang

Huang

Hou

et al. 2017

Bone & Joint Research

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ObjectivesSeveral genome-wide association studies (GWAS) of bone mineral density (BMD) have successfully identified multiple susceptibility genes, yet isolated susceptibility genes are often difficult to interpret biologically. The aim of this study was to unravel the genetic background of BMD at pathway level, by integrating BMD GWAS data with genome-wide expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (meQTLs) dataMethodWe employed the GWAS datasets of BMD from the Genetic Factors for Osteoporosis Consortium (GEFOS), analysing patients’ BMD. The areas studied included 32 735 femoral necks, 28 498 lumbar spines, and 8143 forearms. Genome-wide eQTLs (containing 923 021 eQTLs) and meQTLs (containing 683 152 unique methylation sites with local meQTLs) data sets were collected from recently published studies. Gene scores were first calculated by summary data-based Mendelian randomisation (SMR) software and meQTL-aligned GWAS results. Gene set enrichment analysis (GSEA) was then applied to identify BMD-associated gene sets with a predefined significance level of 0.05.ResultsWe identified multiple gene sets associated with BMD in one or more regions, including relevant known biological gene sets such as the Reactome Circadian Clock (GSEA p-value = 1.0 × 10-4 for LS and 2.7 × 10-2 for femoral necks BMD in eQTLs-based GSEA) and insulin-like growth factor receptor binding (GSEA p-value = 5.0 × 10-4 for femoral necks and 2.6 × 10-2 for lumbar spines BMD in meQTLs-based GSEA).ConclusionOur results provided novel clues for subsequent functional analysis of bone metabolism, and illustrated the benefit of integrating eQTLs and meQTLs data into pathway association analysis for genetic studies of complex human diseases.Cite this article: W. Wang, S. Huang, W. Hou, Y. Liu, Q. Fan, A. He, Y. Wen, J. Hao, X. Guo, F. Zhang. Integrative analysis of GWAS, eQTLs and meQTLs data suggests that multiple gene sets are associated with bone mineral density. Bone Joint Res 2017;6:572–576.

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Skeletal effects of growth hormone and insulin-like growth factor-I therapy

Cited by 38 publications

References 249 publications

Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche

Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche

Muscle–Bone Crosstalk: Emerging Opportunities for Novel Therapeutic Approaches to Treat Musculoskeletal Pathologies

Integrative analysis of GWAS, eQTLs and meQTLs data suggests that multiple gene sets are associated with bone mineral density

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