Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

Russell, Patricia K; Clarke, Michele V; Cheong, Karey; Anderson, Paul; Morris, Howard A.; Wiren, Kristine M.; Zajac, Jeffrey D; Davey, Rachel A

doi:10.1002/jbmr.2413

Cited by 19 publications

(17 citation statements)

References 48 publications

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“…Androgens play a major role in the gain of bone mass during puberty . Androgen actions via AR in osteoblasts inhibit bone resorption in the cancellous compartment and are essential for trabecular bone accrual during growth . On the other hand, the presence of AR in murine osteoclasts is doubtful and certainly does not exert antiresorptive actions .…”

Section: Discussionmentioning

confidence: 99%

“…(1) Androgen actions via AR in osteoblasts inhibit bone resorption in the cancellous compartment and are essential for trabecular bone accrual during growth. (5,6,33) On the other hand, the presence of AR in murine osteoclasts is doubtful and certainly does not exert antiresorptive actions. (5,7) Regarding the cortical compartment, the full action of androgens on periosteal formation requires ERa in addition to AR signaling, as evidenced in studies using AR-ERa double-knockout male mice.…”

Section: Discussionmentioning

confidence: 99%

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Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Jardí

Kim

Laurent

et al. 2018

Journal of Bone and Mineral Research

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Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen‐inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1‐CreERT2‐positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N‐ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic‐pituitary‐gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N‐ARKO mice. However, 36‐ and 46‐week‐old N‐ARKO mice displayed an accelerated age‐related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L5 vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36‐week‐old N‐ARKO mice. Cortical bone loss in N‐ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Jardí

Kim

Laurent

et al. 2018

Journal of Bone and Mineral Research

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“…The femoral microarchitecture of global CTRKO mice, control mice, and their offspring was evaluated using a microtomographic imaging system (Skyscan 1174). The micro-computed tomography (CT) scanning parameters were described previously (25). Cortical parameters were determined in a 0.65-mm region of cortical bone, equivalent to 100 CT slices, centered on a CT slice located one third of the total femoral length from the distal end.…”

Section: Bone Analysesmentioning

confidence: 99%

A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis

et al. 2015

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During lactation, the large transfer of calcium from the mother to the milk is primarily sourced from the maternal skeleton. To determine whether the calcitonin receptor (CTR) plays a physiological role to protect the skeleton from excessive resorption during lactation, we assessed the maternal skeleton of global CTR knockout (CTRKO) and littermate control mice at the end of lactation (postnatal day 21). Micro-computed tomography analyses showed no effect on trabecular or cortical bone in the distal femur and L1 vertebra of maternal global CTR deletion at the end of lactation in global CTRKO mice compared with that in control mice. Bone resorption, as assessed by osteoclast number and activity at the end of lactation, was unaffected by maternal CTR deletion. Cathepsin K, carbonic anhydrase 2, matrix metalloproteinase 13, and receptor activator of nuclear factor-κB ligand mRNA levels, however, were markedly elevated by 3- to 6.5-fold in whole bone of lactating global CTRKO females. Because these genes have been shown to be up-regulated in osteocytes during lactation when osteocytes resorb their surrounding bone matrix, together with their reported expression of the CTR, we determined the osteocyte lacunar area in cortical bone. After lactation, the top 20% of osteocyte lacunar area in global CTRKO mice was 10% larger than the top 20% in control mice. These data are consistent with an increased osteocytic osteolysis in global CTRKO mice during lactation, which is further supported by the increased serum calcium observed in global CTRKO mice after lactation. These results provide evidence for a physiological role for the CTR to protect the maternal skeleton during lactation by a direct action on osteocytes to inhibit osteolysis.

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“…Wild-type (WT) and Global-ARKO littermate controls were included in all analyses (n = 8-15 per group). The PCR protocols used for genotyping the WT, Global-ARKO, PC-AR and mOBL-AR Gene Replacement mice have been described previously (Russell et al 2015).…”

Section: Generation Of Bone Marrow Progenitor Cell-ar Gene Replacemenmentioning

confidence: 99%

“…Therefore, in order to determine whether androgens can act in mesenchymal PCs residing in the bone marrow to influence fat deposition and metabolism in male mice in vivo, we generated a genetically modified mouse model in which the AR gene is replaced specifically in bone marrow mesenchymal PCs of Global-ARKO mice (PC-AR Gene Replacements) (Russell et al 2015). These mesenchymal PCs are pluripotent and can differentiate into osteoprogenitors, osteoblast and osteocytes as well as adipocytes, chondrocytes and myoblasts.…”

Section: Introductionmentioning

confidence: 99%

The androgen receptor in bone marrow progenitor cells negatively regulates fat mass

Russell

Mangiafico

Fam

et al. 2018

Journal of Endocrinology

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It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50-80% lower than wild-type (WT) and 75-90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.

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Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

Cited by 19 publications

References 48 publications

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

A Role for the Calcitonin Receptor to Limit Bone Loss During Lactation in Female Mice by Inhibiting Osteocytic Osteolysis

The androgen receptor in bone marrow progenitor cells negatively regulates fat mass

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