Glucocorticoid excess causes bone loss due to decreased bone formation and increased bone resorption; miR-433-3p is a microRNA (miRNA) that negatively regulates bone formation in male mice by targeting Runx2 as well as RNAs involved in Wnt, protein kinase A, and endogenous glucocorticoid signaling. To examine the impact of miR-433-3p on glucocorticoid-mediated bone loss, transgenic mice expressing a miR-433-3p tough decoy inhibitor in the osteoblast lineage were administered prednisolone via slow-release pellets. Bone loss was greater in control mice treated with prednisolone compared with miR-433-3p tough decoy mice due to higher osteoclast activity in the controls. In whole femurs, Rankl was significantly higher in prednisolone-treated controls compared with miR-433-3p tough decoy mice. Surprisingly, negative regulators of Wnt signaling Sost and Dkk1 were higher in miR-433-3p tough decoy mice and were unaffected by prednisolone. Luciferase- 3'-untranslated region reporter assays demonstrated that Sost is a novel miR-433-3p target, whereas Dkk1 is a previously validated miR-433-3p target. miR-433-3p levels are lower in matrix-synthesizing osteoblasts than in more osteocytic cells; thus the impact of miR-433-3p on the osteoblast lineage may be dependent on cell context: it is a negative regulator in matrix-depositing osteoblasts by targeting RNAs important for differentiation and function but a positive regulator in osteocytes, due to its ability to target prominently expressed negative regulators of Wnt signaling, Sost and Dkk1. The mechanisms by which miR-433-3p indirectly regulates glucocorticoid-mediated osteoclastogenesis remain unknown. However, we speculate that this regulation may be mediated by miR-433-3p activity in osteocytes, which play an important role in controlling osteoclastogenesis.

Bone marrow adipose tissue (BMAT) in the skeleton likely plays a variety of physiological and pathophysiological roles that are not yet fully understood. In elucidating the complex relationship between bone and BMAT, glucocorticoids (GCs) are positioned to play a key role, as they have been implicated in the differentiation of bone marrow mesenchymal stem cells (BMSCs) between osteogenic and adipogenic lineages. The purpose of this review is to illuminate aspects of both endogenous and exogenous GC signaling, including the influence of GC receptors, in mechanisms of bone aging including relationships to BMAT.

Harmful effects of GCs on bone mass involve several cellular pathways and events that can include BMSC differentiation bias toward adipogenesis and the influence of mature BMAT on bone remodeling through crosstalk. Interestingly, BMAT involvement remains poorly explored in GC-induced osteoporosis and warrants further investigation. This review provides an update on the current understanding of the role of glucocorticoids in the biology of osteoblasts and bone marrow adipocytes (BMAds).

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents. However, their clinical usage is limited by severe multisystemic side effects. Glucocorticoid induced osteoporosis results in significant morbidity and mortality but the cellular and molecular mechanisms underlying GC-induced bone loss are not clear. GC use results in decreased osteoblast differentiation with increased marrow adiposity through effects on bone marrow stem cells. GC effects are transduced through its receptor (GR). To identify novel GR regulated genes, we performed RNA sequencing (RNA-Seq) analysis comparing conditional GR knockout mouse made by crossing the floxed GR animal with the Col I promoter-Cre, versus normal floxed GR without Cre, and that testing was specific for Col I promoter active cells, such as bone marrow mesenchymal stem/osteoprogenitor cells (MSCs) and osteoblasts. Results showed 15 upregulated genes (3- to 10-fold) and 70 downregulated genes (-2.7- to -10-fold), with the long noncoding RNA X-inactive specific transcript (Xist) downregulated the most. The differential expression of genes measured by RNA-Seq was validated by qRT-PCR analysis of selected genes and the GC/GR signaling-dependent expression of Xist was further demonstrated by GC (dexamethasone) treatment of GR-deficient MSCs in vitro and by GC injection of C57BL/6 mice (wild-type males and females) in vivo. Our data revealed that the long noncoding RNA Xist is a GR regulated gene and its expression is induced by GC both in vitro and in vivo. To our knowledge, this is the first evidence showing that Xist is transcriptionally regulated by GC/GR signaling.

MicroRNAs (miRNAs) are key posttranscriptional regulators of osteoblastic commitment and differentiation. miR-433-3p was previously shown to target Runt-related transcription factor 2 (Runx2) and to be repressed by bone morphogenetic protein (BMP) signaling. Here, we show that miR-433-3p is progressively decreased during osteoblastic differentiation of primary mouse bone marrow stromal cells in vitro, and we confirm its negative regulation of this process. Although repressors of osteoblastic differentiation often promote adipogenesis, inhibition of miR-433-3p did not affect adipocyte differentiation in vitro. Multiple pathways regulate osteogenesis. Using luciferase-3' untranslated region (UTR) reporter assays, five novel miR-433-3p targets involved in parathyroid hormone (PTH), mitogen-activated protein kinase (MAPK), Wnt, and glucocorticoid signaling pathways were validated. We show that Creb1 is a miR-433-3p target, and this transcription factor mediates key signaling downstream of PTH receptor activation. We also show that miR-433-3p targets hydroxysteroid 11-β dehydrogenase 1 (Hsd11b1), the enzyme that locally converts inactive glucocorticoids to their active form. miR-433-3p dampens glucocorticoid signaling, and targeting of Hsd11b1 could contribute to this phenomenon. Moreover, miR-433-3p targets R-spondin 3 (Rspo3), a leucine-rich repeat-containing G-protein coupled receptor (LGR) ligand that enhances Wnt signaling. Notably, Wnt canonical signaling is also blunted by miR-433-3p activity. In vivo, expression of a miR-433-3p inhibitor or tough decoy in the osteoblastic lineage increased trabecular bone volume. Mice expressing the miR-433-3p tough decoy displayed increased bone formation without alterations in osteoblast or osteoclast numbers or surface, indicating that miR-433-3p decreases osteoblast activity. Overall, we showed that miR-433-3p is a negative regulator of bone formation in vivo, targeting key bone-anabolic pathways including those involved in PTH signaling, Wnt, and endogenous glucocorticoids. Local delivery of miR-433-3p inhibitor could present a strategy for the management of bone loss disorders and bone defect repair. © 2021 American Society for Bone and Mineral Research (ASBMR).

The study investigated the effects of long-term glucocorticoid (GC) administration on bone remodelling, microstructure, and biomechanical strength in cortical and cancellous (trabecular) bones. Thirty-one female Sprague-Dawley rats were randomly divided into three dexamethasone (Dex) dosage groups, 1.0, 2.5, and 5.0 mg/kg twice a week for 8 weeks, and one control group treated with saline. At the end of the experiment, the tibia of one side and the fourth lumbar vertebrae were processed into sections for a histomorphometric analysis, while the femur of the same side and the fifth vertebrae were isolated for a biomechanical test. A dose-dependent decline in bone formation was observed in both trabecular and cortical (periosteal and endosteal) bones. In contrast, bone resorption was inhibited only in cancellous bone in the two higher dose groups and not dose-related. The ratio of Node/Termini increased, while marrow star volume (MSV) decreased in all Dex groups in metaphyseal trabecular bones, both of which were dose-dependent. Subendosteal cortex porosity increased in parallel with non-uniform trabecular distribution, but cortical thickness remained unchanged. Interestingly, there were no significant changes in microstructure or mechanical strength in lumbar trabecular bone. The cortical elastic load was dose-independently reduced in all three Dex groups when compared with the control group. In summary, bone remodelling was dose-dependently inhibited in cancellous bones but enhanced in intracortical bones. The non-uniform distribution of trabecular bone and increased porosity in the inner edge of cortical bone were both in parallel with GC dosage, and the porosity increase was more likely to occur, leading to reduced cortical mechanical strength.

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice (MC2R ^-/- mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R ^-/- mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R ^-/- mice. Based on these observations, bone mineral density of femur in MC2R ^-/- mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R ^-/- mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R ^-/- mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R ^-/- mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.

Clinically, glucocorticoids (GCs) are widely used to treat inflammation-related diseases; however, their long-term use causes side effects, such as osteoporosis and predisposition to bone fractures, known as glucocorticoid-induced osteoporosis (GIOP). Nr3c1 is the major glucocorticoid receptor, and its downstream signaling pathway is involved in regulating various intracellular physiological processes, including those related to bone cells; however, its mechanism in glucocorticoid-induced osteoporosis (GIOP) remains unclear. In this study, a zebrafish nr3c1-mutant was successfully generated using CRISPR/Cas9 technology to investigate the role of nr3c1 in GIOP. Mutations in nr3c1 altered cartilage development and significantly decreased bone mineralization area. Additionally, qRT-PCR results showed that the expression of extracellular matrix-, osteoblast-, and osteoclast-related genes was altered in the nr3c1-mutant. The GC-Nr3c1 pathway regulates the expression of extracellular matrix-, osteoblast-, and osteoclast-related genes via Nr3c1-dependent and Nr3c1-independent pathways. A dual-luciferase reporter assay further revealed that GCs and Nr3c1 transcriptionally regulate matrix metalloproteinase 9 (mmp9), alkaline phosphatase (alp), and acid phosphatase 5a (acp5a). This study reveals that GCs/Nr3c1 affect the expression of genes involved in bone metabolism and provides a basis to determine the role of GIOP and Nr3c1 in bone metabolism and development. We also identified a new effector target for the clinical treatment of GIOP.

Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging.

Administration of glucocorticoids is an effective strategy for treating many inflammatory and autoimmune diseases. However, glucocorticoid treatment can have adverse effects on bone, leading to glucocorticoid-induced osteoporosis (GIO), the most common form of secondary osteoporosis. Although the pathogenesis of GIO has been studied for decades, over the past ten years the autophagy machinery has been implicated as a novel mechanism. Autophagy in osteoblasts, osteocytes, and osteoclasts plays a critical role in the maintenance of bone homeostasis. Herein, we specifically discuss how osteoblast autophagy responds to glucocorticoids and its role in the development of GIO.

Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. Additionally, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess, but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article examines (1) the role of endogenous glucocorticoids in normal bone physiology, (2) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing disease/syndrome and autonomous cortisol secretion (subclinical Cushing syndrome), and (3) the actions of therapeutic (exogenous) glucocorticoids on bone. We review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolizing enzymes and glucocorticoid receptor expression and sensitivity. We consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However, in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.

In this article we used an FDA-approved biodegradable biomaterial, poly (lactic-co-glycolic acid) (PLGA 75:25) to generate a bilayered scaffold with the capacity to induce differential, layer-specific dentinogenic differentiation of dental pulp stem cells (DPSCs) in vitro. We surmise that such a scaffold can be used in conjunction with current regenerative endodontic procedures to help regenerating a physiologic dentin-pulp complex in vivo. We hypothesize that our scaffold in conjunction with DPSCs will advance current regenerative endodontics by restoring dentin and initiating the innervation and revascularization of the pulp.

Abstracts Objective: This study investigated the characteristics of bone microstructure, metabolism, and biomechanics in rat's lumbar vertebra undergoing short-term glucocorticoid administration. Methods: Forty 4-month-old female Sprague-Dawley rats were treated with either vehicle (Cont) or prednisone acetate (Pre) at 3.5 mg/kg/day, respectively for periods of 7 days and 21 days. The lumbar vertebras were processed for MicroCT scan, histomorphometry analysis, mechanical compression test, in addition to Dual-Energy X-ray absorptiometry scan, respectively. Results: The connective density (Conn. D) along with trabecular connection nodes decreased while trabecular termini increased in Pre at day 21 when compared to Cont at day 21 as well as Pre at day 0. The mineralizing surface (MS/BS), mineral apposition rate (MAR), bone formation rate (BFR), osteoblast surfaces (Ob.S/BS) were lower in Pre at day 21 than that in Cont at day 21, Pre at day 0 and Pre at day 7. Only the bending stiffness of compression test decreased in Pre group at day 21 compared to age-matched control. Conclusion: The results suggested that excess prednisone significantly inhibited bone formation and slightly depressed bone resorption in the lumbar vertebra of intact rats for the duration of 21 days. Accordingly, the trabecular spatial microstructure made an adjustment yet failed to maintain the anti-compression mechanical property.

Glucocorticoids (GC), produced and released by the adrenal glands, regulate numerous physiological processes in a wide range of tissues. Because of their profound immunosuppressive and anti-inflammatory actions, GC are extensively used for the treatment of immune and inflammatory conditions, the management of organ transplantation, and as a component of chemotherapy regimens for cancers. However, both pathologic endogenous elevation and long-term use of exogenous GC are associated with severe adverse effects. In particular, excess GC has devastating effects on the musculoskeletal system. GC increase bone resorption and decrease formation leading to bone loss, microarchitectural deterioration and fracture. GC also induce loss of muscle mass and strength leading to an increased incidence of falls. The combined effects on bone and muscle account for the increased fracture risk with GC. This review summarizes the advance in knowledge in the last two decades about the mechanisms of action of GC in bone and muscle and the attempts to interfere with the damaging actions of GC in these tissues with the goal of developing more effective therapeutic strategies.

Glucocorticoids (GCs) are the final effector products of a neuroendocrine HPA/HPI axis governing energy balance and stress response in vertebrates. From a physiological point of view, basal GC levels are essential for intermediary metabolism and participate in the development and homeostasis of a wide range of body tissues, including the skeleton. Numerous mammalian studies have demonstrated that GC hormones exert a positive role during bone modeling and remodeling as they promote osteoblastogenesis to maintain the bone architecture. Although the pharmacological effect of the so-called stress hormones has been widely reported, the role of endogenous GCs on bone mineral metabolism as result of the endocrine stress response has been largely overlooked across vertebrates. In addition, stress responses are variable depending on the stressor (e.g., starvation, predation, and environmental change), life cycle events (e.g., migration and aging), and differ among vertebrate lineages, which react differently according to their biological, social and cognitive complexity (e.g., mineral demands, physical, and psychological stress). This review intends to summarize the endogenous GCs action on bone metabolism of mammals and fish under a variety of challenging circumstances. Particular emphasis will be given to the regulatory loop between GCs and the parathyroid hormone (PTH) family peptides, and other key regulators of mineral homeostasis and bone remodeling in vertebrates.

Individuals with Hajdu-Cheney syndrome (HCS) present with osteoporosis, and HCS is associated with NOTCH2 mutations causing deletions of the proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain that are predicted to enhance NOTCH2 stability and cause gain-of-function. Previously, we demonstrated that mice harboring Notch2 mutations analogous to those in HCS (Notch2HCS) are severely osteopenic because of enhanced bone resorption. We attributed this phenotype to osteoclastic sensitization to the receptor activator of nuclear factor-κB ligand and increased osteoblastic tumor necrosis factor superfamily member 11 (Tnfsf11) expression. Here, to determine the individual contributions of osteoclasts and osteoblasts to HCS osteopenia, we created a conditional-by-inversion (Notch2^COIN ) model in which Cre recombination generates a Notch2^ΔPEST allele expressing a Notch2 mutant lacking the PEST domain. Germ line Notch2^COIN inversion phenocopied the Notch2HCS mutant, validating the model. To activate Notch2 in osteoclasts or osteoblasts, Notch2^COIN mice were bred with mice expressing Cre from the Lyz2 or the BGLAP promoter, respectively. These crosses created experimental mice harboring a Notch2^ΔPEST allele in Cre-expressing cells and control littermates expressing a wild-type Notch2 transcript. Notch2^COIN inversion in Lyz2-expressing cells had no skeletal consequences and did not affect the capacity of bone marrow macrophages to form osteoclasts in vitro In contrast, Notch2^COIN inversion in osteoblasts led to generalized osteopenia associated with enhanced bone resorption in the cancellous bone compartment and with suppressed endocortical mineral apposition rate. Accordingly, Notch2 activation in osteoblast-enriched cultures from Notch2^COIN mice induced Tnfsf11 expression. In conclusion, introduction of the HCS mutation in osteoblasts, but not in osteoclasts, causes osteopenia.

Osteoporosis is among the most devastating side effects of glucocorticoid (GC) therapy for the management of inflammatory and auto-immune diseases. Evidence from both humans and mice indicate deleterious skeletal effects within weeks of pharmacological GC administration, both related and unrelated to a decrease in bone mineral density (BMD). Osteoclast numbers and bone resorption are also rapidly increased, and together with osteoblast inactivation and decreased bone formation, these changes lead the fastest loss in BMD during the initial disease phase. Bone resorption then decreases to sub-physiological levels, but persistent and severe inhibition of bone formation leads to further bone loss and progressively increased fracture risk, up to an order of magnitude higher than that observed in untreated individuals. Bone forming osteoblasts are thus considered the main culprits in GC-induced osteoporosis (GIO). Accordingly, we focus this review primarily on deleterious effects on osteoblasts: inhibition of cell replication and function and acceleration of apoptosis. Mediating these adverse effects, GCs target pivotal regulatory mechanisms that govern osteoblast growth, differentiation and survival. Specifically, GCs inhibit growth factor pathways, including Insulin Growth Factors, Growth Hormone, Hepatocyte Growth/Scatter Factor and IL6-type cytokines. They also inhibit downstream kinases, including PI3-kinase and the MAP kinase ERK, the latter attributable in part to direct transcriptional stimulation of MAP kinase phosphatase 1. Most importantly, however, GCs inhibit the Wnt signaling pathway, which plays a pivotal role in osteoblast replication, function and survival. They transcriptionally stimulate expression of Wnt inhibitors of both the Dkk and Sfrp families, and they induce reactive oxygen species (ROS), which result in loss of ß-catenin to ROS-activated FoxO transcription factors. Identification of dissociated GCs, which would suppress the immune system without causing osteoporosis, is proving more challenging than initially thought, and GIO is currently managed by co-treatment with bisphosphonates or PTH. These drugs, however, are not ideally suited for GIO. Future therapeutic approaches may aim at GC targets such as those mentioned above, or newly identified targets including the Notch pathway, the AP-1/Il11 axis and the osteoblast master regulator RUNX2.

Glucocorticoids (GCs) have both anabolic and catabolic effects on bone. However, no GC anabolic effect mediator has been identified to date. Here we show that targeted expression of glucocorticoid-induced leucine zipper (GILZ), a GC anti-inflammatory effect mediator, enhances bone acquisition in mice. Transgenic mice, in which the expression of GILZ is under the control of a 3.6-kb rat type I collagen promoter, exhibited a high bone mass phenotype with significantly increased bone formation rate and osteoblast numbers. The increased osteoblast activity correlates with enhanced osteogenic differentiation and decreased adipogenic differentiation of bone marrow stromal cell cultures in vitro. In line with these changes, the mRNA levels of key osteogenic regulators (Runx2 and Osx) increased, and the level of adipogenic regulator peroxisome proliferator-activated receptor (PPAR) γ2 decreased significantly. We also found that GILZ physically interacts with C/EBPs and disrupts C/EBP-mediated PPARγ gene transcription. In conclusion, our results showed that GILZ is capable of increasing bone acquisition in vivo, and this action is mediated via a mechanism involving the inhibition of PPARγ gene transcription and shifting of bone marrow MSC/progenitor cell lineage commitment in favor of the osteoblast pathway.

Glucocorticoids (GCs) are highly effective in the treatment of inflammatory and autoimmune conditions but their therapeutic use is limited by numerous adverse effects. Recent insights into the mechanisms of action of both endogenous and exogenous GCs on bone cells have unlocked new approaches to the development of effective strategies for the prevention and treatment of GC-induced osteoporosis. Furthermore, topical studies in rodents indicate that the osteoblast-derived peptide, osteocalcin, plays a central role in the pathogenesis of GC-induced diabetes and obesity. These exciting findings mechanistically link the detrimental effects of GCs on bone and energy metabolism. In this article we review the physiology and pathophysiology of GC action on bone cells, and discuss current and emerging concepts regarding the molecular mechanisms underlying adverse effects of GCs such as osteoporosis and diabetes.

Glucocorticoids are widely used for their unsurpassed anti-inflammatory and immunomodulatory effects. However, the therapeutic use of glucocorticoids is almost always limited by substantial adverse outcomes such as osteoporosis, diabetes, and obesity. These unwanted outcomes are a major dilemma for clinicians because improvements in the primary disorder seem to be achievable only by accepting substantial adverse effects that are often difficult to prevent or treat. To understand the pathogenesis of glucocorticoid-induced osteoporosis, it is necessary to consider that the actions of glucocorticoids on bone and mineral metabolism are strongly dose and time dependent. At physiological concentrations, endogenous glucocorticoids are key regulators of mesenchymal cell differentiation and bone development, with additional regulatory roles in renal and intestinal calcium handling. However, at supraphysiological concentrations, glucocorticoids affect the same systems in different and often unfavourable ways. For many years, these anabolic and catabolic actions of glucocorticoids on bone were deemed paradoxical. In this Review, we highlight recent advances in our understanding of the mechanisms underlying the physiology and pathophysiology of glucocorticoid action on the skeleton and discuss present and future management strategies for glucocorticoid-induced osteoporosis.

The contribution of remodeling-based bone formation coupled to osteoclast activity versus modeling-based bone formation that occurs independently of resorption, to the anabolic effect of PTH remains unclear. We addressed this question using transgenic mice with activated PTH receptor signaling in osteocytes that exhibit increased bone mass and remodeling, recognized skeletal effects of PTH elevation. Direct inhibition of bone formation was accomplished genetically by overexpressing the Wnt antagonist Sost/sclerostin; and resorption-dependent bone formation was inhibited pharmacologically with the bisphosphonate alendronate. We found that bone formation induced by osteocytic PTH receptor signaling on the periosteal surface depends on Wnt signaling but not on resorption. In contrast, bone formation on the endocortical surface results from a combination of Wnt-driven increased osteoblast number and resorption-dependent osteoblast activity. Moreover, elevated osteoclasts and intracortical/calvarial porosity is exacerbated by overexpressing Sost and reversed by blocking resorption. Furthermore, increased cancellous bone is abolished by Wnt inhibition but further increased by blocking resorption. Thus, resorption induced by PTH receptor signaling in osteocytes is critical for full anabolism in cortical bone, but tempers bone gain in cancellous bone. Dissecting underlying mechanisms of PTH receptor signaling would allow targeting actions in different bone compartments, enhancing the therapeutic potential of the pathway.

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

Glucocorticoids are used for treating a wide range of diseases including inflammation and autoimmune disorders. However, there are drawbacks, primarily due to adverse effects on bone cells resulting in osteoporosis. Evidence indicates that the ratio of benefits to adverse effects depends greatly on glucocorticoid receptor (GR)-mediated mechanisms. Delineating GR-mediated signaling in bone cells will allow development of selective GR ligands/agonists (SEGRAs), which would dissociate the positive therapeutic (anti-inflammatory) effects from the negative effects on the skeleton. The present review provides an in-depth account of the current knowledge of GR-mediated transcriptional regulation of specific genes and proteins engaged in the proliferation, differentiation, and apoptosis of bone cells (osteoblasts, osteocytes, osteoclasts). We hope this knowledge will advance research in the development of SEGRAs with improved benefit/risk ratios.