Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response.

Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.

Transferrin receptor 2 mitigates periodontitis-driven alveolar bone loss.

Periodontitis is associated with significant alveolar bone loss. Patients with iron overload suffer more frequently from periodontitis, however, the underlying mechanisms remain largely elusive. Here, we investigated the role of transferrin receptor 2 (Tfr2), one of the main regulators of iron homeostasis, in the pathogenesis of periodontitis and the dental phenotype under basal conditions in mice. As Tfr2 suppresses osteoclastogenesis, we hypothesized that deficiency of Tfr2 may exacerbate periodontitis-induced bone loss. Mice lacking Tfr2 (Tfr2-/- ) and wild-type (Tfr2+/+ ) littermates were challenged with experimental periodontitis. Mandibles and maxillae were collected for microcomputed tomography and histology analyses. Osteoclast cultures from Tfr2+/+ and Tfr2-/- mice were established and analyzed for differentiation efficiency, by performing messenger RNA expression and protein signaling pathways. After 8 days, Tfr2-deficient mice revealed a more severe course of periodontitis paralleled by higher immune cell infiltration and a higher histological inflammation index than Tfr2+/+ mice. Moreover, Tfr2-deficient mice lost more alveolar bone compared to Tfr2+/+ littermates, an effect that was only partially iron-dependent. Histological analysis revealed a higher number of osteoclasts in the alveolar bone of Tfr2-deficient mice. In line, Tfr2-deficient osteoclastic differentiation ex vivo was faster and more efficient as reflected by a higher number of osteoclasts, a higher expression of osteoclast markers, and an increased resorptive activity. Mechanistically, Tfr2-deficient osteoclasts showed a higher p38-MAPK signaling and inhibition of p38-MAPK signaling in Tfr2-deficient cells reverted osteoclast formation to Tfr2+/+ levels. Taken together, our data indicate that Tfr2 modulates the inflammatory response in periodontitis thereby mitigating effects on alveolar bone loss.

Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy.

Cartilage and bone are severely affected by glucocorticoids (GCs), steroid hormones that are frequently used to treat inflammatory diseases. Major complications associated with long-term steroid therapy include impairment of cartilaginous bone growth and GC-induced osteoporosis. Particularly in arthritis, GC application can increase joint and bone damage. Contrarily, endogenous GC release supports cartilage and bone integrity. In the last decade, substantial progress in the understanding of the molecular mechanisms of GC action has been gained through genome-wide binding studies of the GC receptor. These genomic approaches have revolutionized our understanding of gene regulation by ligand-induced transcription factors in general. Furthermore, specific inactivation of GC signaling and the GC receptor in bone and cartilage cells of rodent models has enabled the cell-specific effects of GCs in normal tissue homeostasis, inflammatory bone diseases, and GC-induced osteoporosis to be dissected. In this review, we summarize the current view of GC action in cartilage and bone. We further discuss future research directions in the context of new concepts for optimized steroid therapies with less detrimental effects on bone.

Activation of ß-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice.

Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.

Effects of rigosertib on the osteo-hematopoietic niche in myelodysplastic syndromes.

Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.

Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis.

BACKGROUND: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation. OBJECTIVES: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis. METHODS: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed. RESULTS: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1ß. CONCLUSION: We report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.

Erythropoietin inhibits osteoblast function in myelodysplastic syndromes via the canonical Wnt pathway.

The effects of erythropoietin on osteoblasts and bone formation are controversial. Since patients with myelodysplastic syndromes often display excessively high erythropoietin levels, we aimed to analyze the effect of erythropoietin on osteoblast function in myelodysplastic syndromes and define the role of Wnt signaling in this process. Expression of osteoblast-specific genes and subsequent osteoblast mineralization was increased in mesenchymal stromal cells from healthy young donors by in vitro erythropoietin treatment. However, erythropoietin failed to increase osteoblast mineralization in old healthy donors and in patients with myelodysplasia, whereas the basal differentiation potential of the latter was already significantly reduced compared to that of age-matched controls (P<0.01). This was accompanied by a significantly reduced expression of genes of the canonical Wnt pathway. Treatment of these cells with erythropoietin further inhibited the canonical Wnt pathway. Exposure of murine cells (C2C12) to erythropoietin also produced a dose-dependent inhibition of TCF/LEF promoter activity (maximum at 500 IU/mL, -2.8-fold; P<0.01). The decreased differentiation capacity of erythropoietin-pretreated mesenchymal stromal cells from patients with myelodysplasia could be restored by activating the Wnt pathway using lithium chloride or parathyroid hormone. Its hematopoiesis-supporting capacity was reduced, while reactivation of the canonical Wnt pathway in mesenchymal stromal cells could reverse this effect. Thus, these data demonstrate that erythropoietin modulates components of the osteo-hematopoietic niche in a context-dependent manner being anabolic in young, but catabolic in mature bone cells. Targeting the Wnt pathway in patients with myelodysplastic syndromes may be an appealing strategy to promote the functional capacity of the osteo-hematopoietic niche.

Wnt5a is a key target for the pro-osteogenic effects of iron chelation on osteoblast progenitors.

Iron overload due to hemochromatosis or chronic blood transfusions has been associated with the development of osteoporosis. However, the impact of changes in iron homeostasis on osteoblast functions and the underlying mechanisms are poorly defined. Since Wnt signaling is a critical regulator of bone remodeling, we aimed to analyze the effects of iron overload and iron deficiency on osteoblast function, and further define the role of Wnt signaling in these processes. Therefore, bone marrow stromal cells were isolated from wild-type mice and differentiated towards osteoblasts. Exposure of the cells to iron dose-dependently attenuated osteoblast differentiation in terms of mineralization and osteogenic gene expression, whereas iron chelation with deferoxamine promoted osteogenic differentiation in a time- and dose-dependent manner up to 3-fold. Similar results were obtained for human bone marrow stromal cells. To elucidate whether the pro-osteogenic effect of deferoxamine is mediated via Wnt signaling, we performed a Wnt profiler array of deferoxamine-treated osteoblasts. Wnt5a was amongst the most highly induced genes. Further analysis revealed a time- and dose-dependent induction of Wnt5a being up-regulated 2-fold after 48 h at 50 µM deferoxamine. Pathway analysis using specific inhibitors revealed that deferoxamine utilized the phosphatidylinositol-3-kinase and nuclear factor of activated T cell pathways to induce Wnt5a expression. Finally, we confirmed the requirement of Wnt5a in the deferoxamine-mediated osteoblast-promoting effects by analyzing the matrix mineralization of Wnt5a-deficient cells. The promoting effect of deferoxamine on matrix mineralization in wild-type cells was completely abolished in Wnt5a-/- cells. Thus, these data demonstrate that Wnt5a is critical for the pro-osteogenic effects of iron chelation using deferoxamine.

Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells.

Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA. Furthermore, the resistance of mice expressing a DNA binding-defective GR (GR(dim)) to GC treatment reveals that dimerization of the GR is indispensable for the antiinflammatory effects. In these mice, the GC-induced suppression of T(H)1 and T(H)17 cell-derived proinflammatory cytokines is impaired. Our finding that IL-17A(-/-) mice are resistant to GC therapy, whereas IFN-γ(-/-) mice respond as efficiently as WT mice implies that IL-17-producing T cells and not IFN-γ-producing T cells are the most important targets for an efficient GC therapy. The present study's identification of the critical cell type and the mode of GR action in steroid therapy of AIA significantly advances our understanding of steroid therapy and should lead to therapies with greater efficiency and fewer side effects.

Comparison of the effects of high dietary iron levels on bone microarchitecture responses in the mouse strains 129/Sv and C57BL/6J.

Iron is an essential nutrient for all living organisms. Both iron deficiency and excess can be harmful. Bone, a highly metabolic active organ, is particularly sensitive to fluctuations in iron levels. In this study, we investigated the effects of dietary iron overload on bone homeostasis with a specific focus on two frequently utilized mouse strains: 129/Sv and C57BL/6J. Our findings revealed that after 6 weeks on an iron-rich diet, 129/Sv mice exhibited a decrease in trabecular and cortical bone density in both vertebral and femoral bones, which was linked to reduced bone turnover. In contrast, there was no evidence of bone changes associated with iron overload in age-matched C57BL/6J mice. Interestingly, 129/Sv mice exposed to an iron-rich diet during their prenatal development were protected from iron-induced bone loss, suggesting the presence of potential adaptive mechanisms. Overall, our study underscores the critical role of genetic background in modulating the effects of iron overload on bone health. This should be considered when studying effects of iron on bone.

Effects of dietary iron deficiency or overload on bone: Dietary details matter.

PURPOSE: Bone is susceptible to fluctuations in iron homeostasis, as both iron deficiency and overload are linked to poor bone strength in humans. In mice, however, inconsistent results have been reported, likely due to different diet setups or genetic backgrounds. Here, we assessed the effect of different high and low iron diets on bone in six inbred mouse strains (C57BL/6J, A/J, BALB/cJ, AKR/J, C3H/HeJ, and DBA/2J). METHODS: Mice received a high (20,000 ppm) or low-iron diet (∼10 ppm) after weaning for 6-8 weeks. For C57BL/6J males, we used two dietary setups with similar amounts of iron, yet different nutritional compositions that were either richer ("TUD study") or poorer ("UCLA study") in minerals and vitamins. After sacrifice, liver, blood and bone parameters as well as bone turnover markers in the serum were analyzed. RESULTS: Almost all mice on the UCLA study high iron diet had a significant decrease of cortical and trabecular bone mass accompanied by high bone resorption. Iron deficiency did not change bone microarchitecture or turnover in C57BL/6J, A/J, and DBA/2J mice, but increased trabecular bone mass in BALB/cJ, C3H/HeJ and AKR/J mice. In contrast to the UCLA study, male C57BL/6J mice in the TUD study did not display any changes in trabecular bone mass or turnover on high or low iron diet. However, cortical bone parameters were also decreased in TUD mice on the high iron diet. CONCLUSION: Thus, these data show that cortical bone is more susceptible to iron overload than trabecular bone and highlight the importance of a nutrient-rich diet to potentially mitigate the negative effects of iron overload on bone.

Pten knockout in mouse preosteoblasts leads to changes in bone turnover and strength.

Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in Osterix/Sp7-expressing osteoprogenitor cells were compared to Cre-negative controls. Bone phenotyping was performed by µCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and procollagen type 1 N propeptide (P1NP), and three-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts (P = .00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength (P = .00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of BMSCs.

Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis.

OBJECTIVE: Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload. As iron contributes to inflammatory processes, we investigated whether Tfr2-deletion affects the pathogenesis of inflammatory arthritis in an iron-dependent manner. METHODS: Using a global and conditional genetic disruption of Tfr2, we assessed the relevance of Tfr2 in K/BxN serum-transfer arthritis (STA) and macrophage polarization. RESULTS: Male Tfr2-/- mice subjected to STA developed pronounced joint swelling, and bone erosion as compared to Tfr2+/+ littermate-controls (P < 0.01). Furthermore, an increase of neutrophils and macrophages/monocytes was observed in the inflammatory infiltrate within the paws of Tfr2-/- mice. To elucidate whether Tfr2 in myeloid cells has a direct role in the pathogenesis of arthritis or whether the effects were mediated via the systemic iron overload, we induced STA in Tfr2fl/fl-LysMCre + mice, which showed normal iron-loading. Cre + female mice displayed increased disease development compared to Cre-controls. As macrophages regulate iron availability and innate immunity, we hypothesized that Tfr2-deficiency would polarize macrophages toward a pro-inflammatory state (M1) that contributes to arthritis progression. In response to IFN-γ stimulation, Tfr2-/- macrophages showed increased expression of M1-like cytokines, IFN-γ-target genes, nitric-oxide production, and prolonged STAT1 activation compared to Tfr2+/+ macrophages (P < 0.01), while pre-treatment with ruxolitinib abolished Tfr2-driven M1-like polarization. CONCLUSION: Taken together, these findings suggest a protective role of Tfr2 in macrophages on the progression of arthritis via suppression of M1-like polarization.

Bad to the Bone: The Effects of Therapeutic Glucocorticoids on Osteoblasts and Osteocytes.

Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures - particularly in the spine - thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.

Corrigendum: When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis.

[This corrects the article DOI: 10.3389/fendo.2021.782118.].

Iron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss.

Hereditary hemochromatosis (HH) is a genetic disorder in which mutations affect systemic iron homeostasis. Most subtypes of HH result in low hepcidin levels and iron overload. Accumulation of iron in various tissues can lead to widespread organ damage and to various complications, including liver cirrhosis, arthritis, and diabetes. Osteoporosis is another frequent complication of HH, and the underlying mechanisms are poorly understood. Currently, it is unknown whether iron overload in HH directly damages bone or whether complications associated with HH, such as liver cirrhosis or hypogonadism, affect bone secondarily. This review summarizes current knowledge of bone metabolism in HH and highlights possible implications of metabolic dysfunction in HH-driven bone loss. We further discuss therapeutic considerations managing osteoporosis in HH.

When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management.

Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss.

The Wnt inhibitor Dickkopf-1 (DKK1) is a negative regulator of bone formation and bone mass and is dysregulated in various bone diseases. How DKK1 contributes to postmenopausal osteoporosis, however, remains poorly understood. Here, we show that mice lacking DKK1 in T cells are protected from ovariectomy-induced bone loss. Ovariectomy activated CD4+ and CD8+ T cells and increased their production of DKK1. Co-culture of activated T cells with osteoblasts inhibited Wnt signaling in osteoblasts, leading to impaired differentiation. Importantly, DKK1 expression in T cells also controlled physiological bone remodeling. T-cell-deficient Dkk1 knock-out mice had a higher bone mass with an increased bone formation rate and decreased numbers of osteoclasts compared with controls, a phenotype that was rescued by adoptive transfer of wild-type T cells. Thus, these findings highlight that T cells control bone remodeling in health and disease via their expression of DKK1.

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

CONTEXT: Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide. OBJECTIVE: As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations. DESIGN: We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects. RESULTS: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover. CONCLUSION: Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.

Shaping the bone through iron and iron-related proteins.

Well-controlled iron levels are indispensable for health. Iron deficiency is the most common cause of anemia, whereas iron overload, either hereditary or secondary due to disorders of ineffective erythropoiesis, causes widespread organ failure. Bone is particularly sensitive to fluctuations in systemic iron levels as both iron deficiency and overload are associated with low bone mineral density and fragility. Recent studies have shown that not only iron itself, but also iron-regulatory proteins that are mutated in hereditary hemochromatosis can control bone mass. This review will summarize the current knowledge on the effects of iron on bone homeostasis and bone cell activities, and on the role of proteins that regulate iron homeostasis, i.e. hemochromatosis proteins and proteins of the bone morphogenetic protein pathway, on bone remodeling. As disorders of iron homeostasis are closely linked to bone fragility, deeper insights into common regulatory mechanisms may provide new opportunities to concurrently treat disorders affecting iron homeostasis and bone.