Sex and the single nucleotide polymorphism: Exploring the genetic causes of skeletal sex differences

Nielson, Carrie M.; Klein, Robert F.; Orwoll, Eric

doi:10.1002/jbmr.1723

Cited by 3 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Common and differential gender influences on bone metabolism have been revealed 13,36 . It has been documented that gender differences may be present in human bone development and in peak bone mass, although bone mass accrual before and during puberty can be similar in women and men, Similar age-specific risks of fractures are also observed 37,38 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery

et al. 2018

View full text Add to dashboard Cite

Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences. Using the gonadectomy (GNX) model, we confirmed that the osteoporotic phenotypes were substantially consistent between female and male mice. Importantly, systemic MSC transplantation (MSCT) not only rescued trabecular bone loss in GNX mice but also restored cortical bone mass and bone quality. Unexpectedly, no differences were detected between the genders. Furthermore, MSCT demonstrated an equal efficiency in rectifying the bone remodeling balance in both genders of GNX animals, as proven by the comparable recovery of bone formation and parallel normalization of bone resorption. Mechanistically, using green fluorescent protein (GFP)-based cell-tracing, we demonstrated rapid engraftment but poor inhabitation of donor MSCs in the GNX recipient bone marrow of each gender. Alternatively, MSCT uniformly reduced the CD3+T-cell population and suppressed the serum levels of inflammatory cytokines in reversing female and male GNX osteoporosis, which was attributed to the ability of the MSC to induce T-cell apoptosis. Immunosuppression in the microenvironment eventually led to functional recovery of endogenous MSCs, which resulted in restored osteogenesis and normalized behavior to modulate osteoclastogenesis. Collectively, these data revealed recipient sexually monomorphic responses to MSC therapy in gonadal steroid deficiency-induced osteoporosis via immunosuppression/anti-inflammation and resident stem cell recovery.

show abstract

Section: Discussionmentioning

confidence: 99%

“…However, in osteoporosis triggered by male hypogonadism, the effects of MSCT are still not understood. Actually, gender homogeneity and heterogeneity of the skeleton have long been described or debated 13 . The complicated issues make it difficult to predict whether MSCT exerts gender-specific anti-osteoporotic impacts or not.…”

Section: Introductionmentioning

confidence: 99%

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery

et al. 2018

View full text Add to dashboard Cite

show abstract

“…First, women start with lower bone mineral density (BMD) than their male peers. Heritability of skeletal traits has been demonstrated and many common single nucleotide polymorphisms (SNP) have pointed to genes accounting for variability in BMD and fracture risk (see Commentary by Nielson et al) (1). These observations led to an investigation whether gene variation affects the female skeleton differently than it does the male.…”

mentioning

confidence: 99%

“…Yet, a recent report shows that no gender differences in the effects of autosomal SNPs on BMD were found in analyses of more than 50,000 men and women. (2) Although other genetic features beyond SNPs and BMD can be explored, (1) postnatal factors are important to be considered.…”

mentioning

confidence: 99%

Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis?

Huang

Partridge

2013

Bone

View full text Add to dashboard Cite

Genome-Wide Association Analysis of Longitudinal Bone Mineral Content Data From the Iowa Bone Development Study

Bay

Levy

Janz

et al. 2021

Journal of Clinical Densitometry

View full text Add to dashboard Cite

The foundation for osteoporosis risk is established during the time periods of childhood, adolescence, and young adulthood, periods of development when bone mass is being accrued rapidly. The relative quantity of bone mass accrued is influenced by both lifestyle and genetic factors. The purpose of this dissertation project was to discover single nucleotide polymorphisms (SNPs) associated with: (1) The rate of hip bone accrual (measured as bone mineral content or BMC) during the adolescent growth spurt, and (2) Total hip bone mass measured as BMC around the age of 19 when the amount of bone accrued is approximately at its peak. Additionally, SNP × longitudinal lifestyle factor (calcium intake per day, vitamin D intake per day, and minutes of moderate to vigorous physical activity (MVPA) per day) multiplicative interaction effects were assessed. Each cohort member's vector of longitudinal physical activity measurements was summarized as belonging to one of a set of specific trajectory groups using finite mixture modeling. The same was then done for calcium intake and vitamin D intake. The source of the data utilized was the Iowa Bone Development Study (IBDS), which includes genetic and longitudinal bone measurement information. To discover SNPs, a genome-wide association study (GWAS) design was utilized. Females and males were analyzed separately and together. The association between SNPs and the rate of hip bone accrual during the adolescent growth spurt was assessed using linear mixed models controlling for body size, and the association between SNPs and peak hip bone mass was assessed using an ordinary linear regression model, also controlling for body size. Approximately 500,000 SNPs were tested in each GWA analysis; significance was assessed at a familywise error rate of 0.05, the individual test cutoff of which was determined by using SimpleM, a modified Šídák correction. v No statistically significant SNPs were detected at the 0.05 familywise error rate threshold established by SimpleM (p < 1.76×10-7); however genes near suggestive SNPs (24 total) were assessed for biological relevance. Of most biological relevance were two suggestive SNPs (rs2051756 and rs2866908, p-values of 1.25×10-6 and 4.28×10-6 , respectively) that were detected in an intron of the DKK2 gene through the GWA analysis exploring peak bone mass in females. The DKK2 gene is part of the Wnt signaling pathway and is associated with embryonic development; additionally, it is expressed more highly in osteoarthritic osteoblasts than in normal osteoblasts. No statistically significant results were found from the SNP × lifestyle factor multiplicative interaction effect tests. The potential importance of the DKK2 gene to peak hip bone mass accrual in females should be studied further in order to understand the pathophysiology of this suggested novel association identified during a discovery GWA analysis. vi

show abstract

Sex and the single nucleotide polymorphism: Exploring the genetic causes of skeletal sex differences

Cited by 3 publications

References 34 publications

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery

Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis?

Genome-Wide Association Analysis of Longitudinal Bone Mineral Content Data From the Iowa Bone Development Study

Contact Info

Product

Resources

About