Lrp6 Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd

Low‐density lipoprotein receptor‐related protein 5 (LRP5) regulates bone acquisition by controlling bone formation. Because roles of LRP6, another co‐receptor for Wnts, in postnatal bone metabolism have not been fully elucidated, we studied bone phenotype in mice harboring an Lrp6 hypomorphic mutation, ringelschwanz (rs), and characterized the mutant protein. First, we performed pQCT, bone histomorphometry, and immunohistochemistry on tibias of Lrp6^rs/rs and Lrp6^+/+ mice and determined biochemical parameters for bone turnover. Lrp6^rs/rs mice exhibited reduced trabecular BMD in pQCT. Bone histomorphometry showed low bone volume and decreased trabecular number, which were associated with increased eroded surface. Urinary deoxypyridinoline excretion was increased in Lrp6^rs/rs mice, whereas levels of serum osteocalcin were comparable between Lrp6^rs/rs mice and wildtype littermates. Increase in cell number and mineralization of calvariae‐derived osteoblasts were not impaired in Lrp6^rs/rs osteoblasts. Rankl expression was increased in Lrp6^rs/rs osteoblasts both in vivo and in vitro, and osteoclastogenesis and bone‐resorbing activity in vitro were accelerated in Lrp6^rs/rs cells. Treatment with canonical Wnt suppressed Rankl expression in both in primary osteoblasts and ST2 cells. Overexpression of Lrp6 also suppressed Rankl expression, whereas the Lrp6 rs mutant protein did not. Functional analyses of the Lrp6 rs mutant showed decreased targeting to plasma membrane because of reduced interaction with Mesoderm development (Mesd), a chaperone for Lrp6, leading to impaired Wnt/β‐catenin signaling. These results indicate that Lrp6‐mediated signaling controls postnatal bone mass, at least partly through the regulation of bone resorption. It is also suggested that the interaction with Mesd is critical for Lrp6 to function.     

The Association of Lean Mass and Fat Mass With Peak Bone Mass in Young Premenopausal Women

Total body mass is a major determinant of bone mass, but studies of the relative contributions of lean mass (LM) and fat mass (FM) to bone mass have yielded conflicting results. This is likely because of the use of bone measures that are not adequately adjusted for body size and, therefore, not appropriate for analyses related to body composition, which is also correlated with body size. We examined the relationship between body composition and peak bone mass in premenopausal women aged 18–30 yr using both size-dependent and size-adjusted measures of bone density and body composition, as well as statistical models adjusted for size-related factors. We measured total bone mass and areal bone density using dual-energy X-ray absorptiometry, and used established formulas to calculate estimates of volumetric (size-adjusted) bone density. LM tended to be positively associated with bone both before and after adjustment for size-related factors. FM and body fat percentage, however, were positively associated with size-dependent bone measures, but adjusting for size removed or reversed this association. These findings suggest that the association between bone mass and body composition, especially FM, is dependent on the bone measures analyzed, and that determining the most appropriate size-adjustment techniques is critical for understanding this relationship.     

CD55 Regulates Bone Mass in Mice by Modulating RANKL-Mediated Rac Signaling and Osteoclast Function

CD55 is a glycosylphosphatidylinositol (GPI)-anchored protein that regulates complement-mediated and innate and adaptive immune responses. Although CD55 is expressed in various cell types in the bone marrow, its role in bone has not been investigated. In the current study, trabecular bone volume measured by μCT in the femurs of CD55KO female mice was increased compared to wild type (WT). Paradoxically, osteoclast number was increased in CD55KO with no differences in osteoblast parameters. Osteoclasts from CD55KO mice exhibited abnormal actin-ring formation and reduced bone-resorbing activity. Moreover, macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) treatment failed to activate Rac guanosine triphosphatase (GTPase) in CD55KO bone marrow macrophage (BMM) cells. In addition, apoptotic caspases activity was enhanced in CD55KO, which led to the poor survival of mature osteoclasts. Our results imply that CD55KO mice have increased bone mass due to defective osteoclast resorbing activity resulting from reduced Rac activity in osteoclasts. We conclude that CD55 plays an important role in the survival and bone-resorption activity of osteoclasts through regulation of Rac activity. © 2019 American Society for Bone and Mineral Research.     

Subcutaneous Fat and Body Fat Mass Have Different Effects on Bone Development at the Forearm in Children and Adolescents

The present study investigated whether subcutaneous fat differs in the impact on bone development from fat mass (FM). We analyzed 295 healthy children and adolescents (age 5–19 years, 139 males) for FM by measuring four skinfold thicknesses and for bone development and body composition at the forearm by peripheral quantitative computed tomography in a cross-sectional investigation. Relative cross-sectional fat area (FA) was a surrogate for relative subcutaneous FM at the forearm and was associated positively with percent fat in prepubertal individuals and pubertal females but negatively in pubertal males. Percent FM was associated with trabecular bone mineral density (BMDtrab) in prepubertal individuals (females r = 0.394, males r = 0.242) and pubertal individuals (females r = 0.215, males r = −0.275). Bone mineral count was correlated with percent FM in pubertal males (r = −0.287). FA was correlated with BMDtrab (r = 0.285) and with cortical bone mineral density (BMDcort, r = −0.296) in pubertal females. The ratio FA/FM was negatively correlated with BMDcort (r = −0.299) in pubertal females. Pubertal females with relatively high subcutaneous fat area (high ratio FA/FM) were characterized by lower bone strength (P = 0.047). FM and the relative amount of subcutaneous fat have effects on bone formation and resorption that depend on gender and puberty. Especially in pubertal females, higher levels of subcutaneous fat may decrease bone strength due to increased cortical remodeling.     

Interrelation Among Dietary Energy and Fat Intakes, Maternal Body Fatness, and Milk Total Lipid in Humans

The relationship between maternal dietaryintakes of energy or fat maternal body composition andthe milk fat concentration is an important element inunderstanding the role of breast-milk in infantnutrition. In most studies in both developing anddeveloped countries, no relation between maternal energyintake and milk fat content was observed. In only onepublished study, in which maternal fat intake comprised a very low 5% of calories, was a short termreduction in milk lipid observed in some subjects. Onthe other hand, a positive relation between maternalfatness and milk fat is evident in both well-nourished and under-nourished women when appropriatemethodologies have been used. Low milk fatconcentrations are associated with higher milk volumesprobably because infant demand determines milk intake,compensating, at least partially, for low milk fat. Noimpairment of infant growth was associated with low milkfat, in studies where it has been measured. Themechanism for the relationship between body fat and milk fat is a fertile field for additionalinvestigation.     

Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption

Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled‐hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts derived from wild‐type and Fgfr3‐deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3‐deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3‐deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption. © 2016 American Society for Bone and Mineral Research.     

Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH-Induced Bone Anabolism in Male Mice

Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone-forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate-limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1-mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine-derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro-anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)-induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH-induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Leptin, Fat Mass, and Bone Mineral Density in Healthy Pre- and Postmenopausal Women

The purpose was to examine relationships between age, fat mass, and bone mineral density (BMD) with resting leptin levels in premenopausal and postmenopausal women. Young (aged 18–30 yr, n = 30) and estrogen-deficient postmenopausal (aged 55–75 yr, n = 43) women were recruited. Total body and segmental fat mass and bone-free lean body mass (BFLBM) and total body, lumbar spine, and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Serum-resting, fasted leptin levels were measured by Immunoradiometric Assay (IRMA), and leptin-to-fat mass ratios were calculated. Young and older women had similar amounts of BFLBM, but older women had greater (p < 0.05) amounts of fat mass and 35% higher leptin levels. Age differences in leptin concentrations were no longer significant after controlling for fat mass. Older women had significantly (p < 0.05) lower hip BMD values. Age was negatively related (r = −0.29, p < 0.05) to leptin:trunk fat ratio. Increases in fat mass, not menopause per se, contributes to higher leptin levels in older women. Relationships between leptin and BMD may be age dependent.     

Relative Importance of Lean Mass and Fat Mass on Bone Mineral Density in a Group of Lebanese Postmenopausal Women

The aim of this study was to determine the relative importance of lean mass and fat mass on bone mineral density (BMD) in a group of Lebanese postmenopausal women. One hundred ten Lebanese postmenopausal women (aged 65–84 yr) participated in this study. Age and years since menopause were recorded. Body weight and height were measured and body mass index (BMI) was calculated. Body composition (lean mass, fat mass, and fat mass percentage) was assessed by dual-energy X-ray absorptiometry (DXA). Bone mineral content (BMC) of the whole body (WB) and BMD of the WB, the lumbar spine (L1–L4), the total hip (TH), the femoral neck (FN), the ultra distal (UD) Radius, and the 1/3 Radius were measured by DXA. The expressions WB BMC/height and WB BMD/height were also used. Weight, BMI, fat mass, and lean mass were positively correlated to WB BMC, WB BMC/height, WB BMD/height, and to WB, L1–L4, TH, FN, UD Radius, and 1/3 Radius BMD. However, using multiple linear regression analyses, fat mass was more strongly correlated to BMC and to BMD values than lean mass after controlling for years since menopause. This study suggests that fat mass is a stronger determinant of BMC and BMD than lean mass in Lebanese postmenopausal women.     

Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer

BACKGROUND: The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epidemiologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. METHODS: We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. RESULTS: We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend <0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). CONCLUSIONS: Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.     

Plasma Osteocalcin Is Inversely Related to Fat Mass and Plasma Glucose in Elderly Swedish Men

The osteoblast‐derived protein osteocalcin has recently been shown to affect adiposity and glucose homeostasis in mice, suggesting that the skeleton influences energy metabolism through an endocrine mechanism. The aim of this study was to investigate the relationship between plasma osteocalcin and parameters reflecting fat mass and glucose homeostasis in humans. Fasting levels of plasma osteocalcin, plasma glucose, serum insulin, and lipids were analyzed in elderly men (75.3 ± 3.2 yr of age) in the Gothenburg part (all subjects, n = 1010; nondiabetic, n = 857; diabetic, n = 153) of the MrOS Sweden study. Fat mass and lean mass were analyzed using DXA. Diabetic subjects had lower plasma osteocalcin (?21.7%, p < 0.001) than nondiabetic subjects. For both all subjects and nondiabetic subjects, plasma osteocalcin was clearly inversely related to body mass index (BMI), fat mass, and plasma glucose (p < 0.001), whereas it was not associated with height or lean mass. Plasma osteocalcin explained a substantial part (6.3%) of the variance in plasma glucose, whereas it associated moderately with serum insulin. Multiple linear regression models adjusting for serum insulin and fat mass showed that plasma osteocalcin was an independent negative predictor of plasma glucose (p < 0.001). We herein, for the first time in humans, show that plasma osteocalcin is inversely related to fat mass and plasma glucose. Although one should be cautious with mechanistic interpretations of cross‐sectional association studies, our human data support recently published experimental studies, showing endocrine functions of osteoblast‐derived osteocalcin on glucose and fat homeostasis.     

Enteroendocrine K Cells Exert Complementary Effects to Control Bone Quality and Mass in Mice

The involvement of a gut-bone axis in controlling bone physiology has been long suspected, although the exact mechanisms are unclear. We explored whether glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine K cells were involved in this process. The bone phenotype of transgenic mouse models lacking GIP secretion (GIP-GFP-KI) or enteroendocrine K cells (GIP-DT) was investigated. Mice deficient in GIP secretion exhibited lower bone strength, trabecular bone mass, trabecular number, and cortical thickness, notably due to higher bone resorption. Alterations of microstructure, modifications of bone compositional parameters, represented by lower collagen cross-linking, were also apparent. None of these alterations were observed in GIP-DT mice lacking enteroendocrine K cells, suggesting that another K-cell secretory product acts to counteract GIP action. To assess this, stable analogues of the known K-cell peptide hormones, xenin and GIP, were administered to mature NIH Swiss male mice. Both were capable of modulating bone strength mostly by altering bone microstructure, bone gene expression, and bone compositional parameters. However, the two molecules exhibited opposite actions on bone physiology, with evidence that xenin effects are mediated indirectly, possibly via neural networks. Our data highlight a previously unknown interaction between GIP and xenin, which both moderate gut-bone connectivity. © 2020 American Society for Bone and Mineral Research.     

Mammary Cancer in Humans and Mice: A Tutorial for Comparative Pathology. The CD-ROM

This article introduces a CD-ROM containing whole-mount and histological images of normal growth and development of both the mouse mammary gland and the human breast. It also covers nonneoplastic lesions and neoplasias in both species including a catalog of lesions in genetically engineered mice. Instructions, with examples, on techniques such as whole-mount preparation, immunohistochemistry, in situ hybridization, and common histological stains are provided. The images are based on full-scale 1996 × 1640 pixel images at 300 pixels/inch and are annotated. Every genetically engineered model has one or more accompanying citations. Tables are provided for orientation and organization. The CD includes zoom capabilities, a search engine, and a help mode.     

Altered Bone Material Properties in HLA‐B27 Rats Include Reduced Mineral to Matrix Ratio and Altered Collagen Cross‐Links

Spondyloarthropathy and inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, are often associated with severe osteopenia/osteoporosis in both children and adults. HLA‐B27 transgenic rats present a phenotype that includes severe colitis and severely accelerated alveolar bone loss. The purpose of this study was to evaluate long bone density status, systemic bone metabolic markers, and intrinsic bone material properties in HLA‐B27 transgenic (TG) rats, and compare them with those of age‐ and sex‐matched wild‐type (WT) animals. The results indicate that in the HLA‐B27 rat, an animal susceptible to both alveolar bone loss (ABL) and long bone osteopenia, there is a statistically significant negative correlation between ABL and long bone bone mineral density (BMD), as well as mineral/matrix ratio at active bone‐forming trabecular surfaces. The TG animals had a lower mineral/matrix ratio and higher relative proteoglycan and advanced glycation end product (?‐N‐Carboxymethyl‐L‐lysine) content and pyridinoline/divalent collagen cross‐link ratio compared with WT. These results may provide better understanding of the interrelationship between osteoporosis and oral bone loss, the underlying causes of the inferior bone strength in the HLA‐B27 transgenic animals, and could prove to be a useful model in the elucidation of the pathophysiology of spondyloarthropathy and IBD‐associated osteopenia/osteoporosis and in the evaluation of pharmacological intervention(s) against such conditions. © 2014 American Society for Bone and Mineral Research.     

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

X-linked hypophosphatemia (XLH), caused by a loss-of-function mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX), is the most common form of vitamin D-resistant rickets. Loss of functional PHEX results in elevated fibroblast growth factor 23 (FGF23) levels, impaired phosphate reabsorption, and inhibited skeletal mineralization. Sclerostin, a protein produced primarily in osteocytes, suppresses bone formation by antagonizing Wnt signaling and is reported to be elevated in XLH patients. This study used the Hyp mouse model to investigate sclerostin's role in the pathophysiology of XLH by evaluating the use of a monoclonal antibody to sclerostin in a mouse model of XLH, the Hyp mouse. Male and female wild-type and Hyp littermates were injected with 25 mg/kg of vehicle or sclerostin antibody (Scl-Ab) twice weekly, beginning at 4 weeks of age and euthanized at 8 weeks of age. Scl-Ab treatment increased serum phosphate levels and suppressed circulating levels of intact FGF23 in treated wild-type and Hyp mice of both sexes. Cortical area, trabecular bone volume fraction (BV/TV), metaphyseal apparent density, and the peak load increased with Scl-Ab treatment in both sexes. This short-term treatment study suggests that Scl-Ab treatment can effectively improve some of the pathologies associated with XLH, including normalization of phosphate, and that sclerostin may play a role in regulating FGF23 and phosphate metabolism in XLH. © 2019 American Society for Bone and Mineral Research.     

Changes in Bone Mineral, Lean Body Mass and Fat Content as Measured by Dual Energy X-ray Absorptiometry: A Longitudinal Study

Bone mineral density (BMD) and soft tissue composition were measured by dual energy X-ray absorptiometry (DXA) 3–4 years apart in 273 men and women aged 23–90. We found different rates of BMD loss in different skeletal regions. There were also different rates of BMD loss in different regions within the hip. Average rates of loss for male subjects 50 years of age and above for BMD total body were 0.1%/year and for femoral neck 1.5%/year, whereas lumbar spine (L2–L4) increased by 0.4%/year. Average rates of loss for female subjects 50 years of age and above for BMD total body were 0.0%/year, femoral neck 0.9%/year, and lumbar spine (L2–L4) 0.1%/year. Received: 28 November 1997 / Accepted: 26 July 1999     

Female Mice Lacking Estrogen Receptor‐Alpha in Osteoblasts Have Compromised Bone Mass and Strength

Reduced bioavailability of estrogen increases skeletal fracture risk in postmenopausal women, but the mechanisms by which estrogen regulates bone mass are incompletely understood. Because estrogen signaling in bone acts, in part, through estrogen receptor alpha (ERα), mice with global deletion of ERα (ERαKO) have been used to determine the role of estrogen signaling in bone biology. These animals, however, have confounding systemic effects arising from other organs, such as increased estrogen and decreased insulin‐like growth factor 1 (IGF‐1) serum levels, which may independently affect bone. Mice with tissue‐specific ERα deletion in chondrocytes, osteoblasts, osteocytes, or osteoclasts lack the systemic effects seen in the global knockout, but show that presence of the receptor is important for the function of each cell type. Although bone mass is reduced when ERα is deleted from osteoblasts, no study has determined if this approach reduces whole bone strength. To address this issue, we generated female osteoblast‐specific ERαKO mice (pOC‐ERαKO) by crossing mice expressing a floxed ERα gene (ERα^fl/fl) with mice transgenic for the osteocalcin‐Cre promoter (OC‐Cre). Having confirmed that serum levels of estrogen and IGF‐1 were unaltered, we focused on relating bone mechanics to skeletal phenotype using whole bone mechanical testing, microcomputed tomography, histology, and dynamic histomorphometry. At 12 and 18 weeks of age, pOC‐ERαKO mice had decreased cancellous bone mass in the proximal tibia, vertebra, and distal femur, and decreased cortical bone mass in the tibial midshaft, distal femoral cortex, and L5 vertebral cortex. Osteoblast activity was reduced in cancellous bone of the proximal tibia, but osteoclast number was unaffected. Both femora and vertebrae had decreased whole bone strength in mechanical tests to failure, indicating that ERα in osteoblasts is required for appropriate bone mass and strength accrual in female mice. This pOC‐ERαKO mouse is an important animal model that could enhance our understanding of estrogen signaling in bone cells in vivo. © 2014 American Society for Bone and Mineral Research.     

The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass,Bone Marrow Adipose Tissue,and Systemic Metabolism in Female Mice During Aging

Hallmarks of aging-associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging-associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR-CKO; GR^fl/fl:Osx-Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3- and 6-month-old) mice. GR deficiency in Osx-expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR-CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole-body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR-CKO osteoblastic cultures in a glucocorticoid-dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR-deficient bone on whole-body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).