Stavros C Manolagas

Central Arkansas Veterans Healthcare System, Washington, Washington, D.C., United States

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Publications (235)1808.52 Total impact

  • James A. Carson · Stavros C. Manolagas
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    ABSTRACT: Estrogens and androgens influence the growth and maintenance of bones and muscles and are responsible for their sexual dimorphism. A decline in their circulating levels leads to loss of mass and functional integrity in both tissues. In the article, we highlight the similarities of the molecular and cellular mechanisms of action of sex steroids in the two tissues; the commonality of a critical role of mechanical forces on tissue mass and function; emerging evidence for an interplay between mechanical forces and hormonal and growth factor signals in both bones and muscles; as well as the current state of evidence for or against a cross-talk between muscles and bone. In addition, we review evidence for the parallels in the development of osteoporosis and sarcopenia with advancing age and the potential common mechanisms responsible for the age-dependent involution of these two tissues. Lastly, we discuss the striking difference in the availability of several drug therapies for the prevention and treatment of osteoporosis, as compared to none for sarcopenia.
    No preview · Article · Nov 2015 · Bone
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    ABSTRACT: The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone.
    Full-text · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Activation of Sirtuin1 (Sirt1) - an NAD(+) dependent deacetylase - by natural or synthetic compounds like resveratrol, SRT2104, or SRT3025 attenuates the loss of bone mass caused by ovariectomy, aging, or unloading in mice. Conversely, Sirt1 deletion in osteoclast progenitors increases osteoclast number and bone resorption. Sirt1 deacetylates FoxO1, 3, and 4 and thereby modulates their activity. FoxOs restrain osteoclastogenesis and bone resorption. Here, we tested the hypothesis that the anti-resorptive effects of Sirt1 are mediated by FoxOs. We report that Sirt1 activation by SRT2104 and SRT3025 inhibited murine osteoclast progenitor proliferation and reduced osteoclastogenesis. The effect of Sirt1 stimulators on osteoclastogenesis was abrogated in cells lacking FoxO1, 3, and 4. FoxO1 acetylation was increased by knocking-down Sirt1 or addition of RANKL - the critical cytokine for osteoclast differentiation. Furthermore, acetylation inhibited while deacetylation promoted FoxO-mediated transcription. SRT3025 increased the expression of the FoxO-target genes catalase and hemeoxygenase-1 (HO-1) in osteoclast progenitors, in a FoxO-dependent manner. HO-1 catabolizes heme and attenuates mitochondrial oxidative phosphorylation and ATP production in macrophages. HO-1 levels were strongly reduced and ATP levels increased by RANKL. In contrast, SRT3025 and FoxOs decreased ATP production, and the effect of SRT3025 was mediated by FoxOs. These findings reveal that the anti-osteoclastogenic actions of Sirt1 are mediated by FoxOs and result from impaired mitochondria activity. Along with earlier findings that the osteoblastogenic effects of Sirt1 are also mediated by FoxOs, these results establish that the dual anti-osteoporotic efficacy of Sirt1 stimulators (i.e. decreasing bone resorption and promoting bone formation) is mediated via FoxO deacetylation.
    No preview · Article · Aug 2015 · Molecular Endocrinology
  • Stavros C Manolagas · Juliet Compston · Sudhaker Rao · Ego Seeman
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    ABSTRACT: On May 18, 2015, the Bone and Mineral Community lost Alwyn Michael Parfitt, M.D., one of its giants. Michael's career spanned over fifty years and three different continents and established him as mentor of the field and one of its most transformative figures. His contribution to bone research is unique in its breadth and depth. It is characterized by rigorous scholarship; passion for the subject; refusal to accept established dogma without critical reappraisal; and the ability to generate new concepts that often changed thinking and opened new avenues of exploration. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    ABSTRACT: Glucocorticoid excess decreases bone mass and strength in part by acting directly on osteoblasts and osteocytes, but the mechanisms remain unclear. Macroautophagy (herein referred to as autophagy) is a lysosome-based recycling pathway that promotes the turnover of intracellular components and can promote cell function and survival under stressful conditions. Recent studies have shown that glucocorticoids stimulate autophagy in osteocytes, suggesting that autophagy may oppose the negative actions of glucocorticoids on this cell type. To address this possibility, we compared the impact of prednisolone administration on the skeletons of adult mice in which autophagy was suppressed in osteocytes, via deletion of Atg7 with a Dmp1-Cre transgene, to their control littermates. In control mice, prednisolone increased autophagic flux in osteocyte-enriched bone as measured by LC3 conversion, but this change did not occur in the mice lacking Atg7 in osteocytes. Nonetheless, prednisolone reduced femoral cortical thickness, increased cortical porosity, and reduced bone strength to similar extents in mice with and without autophagy in osteocytes. Prednisolone also suppressed osteoblast number and bone formation in the cancellous bone of control mice. As shown previously, Atg7 deletion in osteocytes reduced osteoblast number and bone formation in cancellous bone, but these parameters were not further reduced by prednisolone administration. In cortical bone, prednisolone elevated osteoclast number to a similar extent in both genotypes. Taken together, these results demonstrate that although glucocorticoids stimulate autophagy in osteocytes, suppression of autophagy in this cell type does not worsen the negative impact of glucocorticoids on the skeleton. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Feb 2015 · Bone
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    ABSTRACT: In men, androgens are critical for the acquisition and maintenance of bone mass in both the cortical and cancellous bone compartment. Male mice with targeted deletion of AR in mature osteoblasts or osteocytes have lower cancellous bone mass, but no cortical bone phenotype. We have investigated the possibility that the effects of androgens on the cortical compartment result from AR signaling in osteo-progenitors or cells of the osteoclast lineage; or via ERα signaling in either or both of these two cell types upon conversion of testosterone to estradiol. To this end, we generated mice with targeted deletion of an AR or an ERα allele in the mesenchymal (AR(f/y) ;Prx1-Cre or ERα(f/f) ;Osx1-Cre) or myeloid cell lineage (AR(f/y) ;LysM-Cre or ERα(f/f) ;LysM-Cre) and their descendants. Male AR(f/y) ;Prx1-Cre mice exhibited decreased bone volume and trabecular number, and increased osteoclast number in the cancellous compartment. Moreover, they did not undergo the loss of cancellous bone volume and trabecular number caused by orchidectomy (ORX) in their littermate controls. In contrast, AR(f/y) ;LysM-Cre, ERα(f/f) ;Osx1-Cre, or ERα(f/f) ;LysM-Cre mice had no cancellous bone phenotype at baseline and lost the same amount of cancellous bone as their controls following ORX. Most unnexpectedly, adult males of all four models had no discernable cortical bone phenotype at baseline, and lost the same amount of cortical bone as their littermate controls following ORX. Recapitulation of the effects of ORX by AR deletion only in the AR(f/y) ;Prx1-Cre mice indicates that the effects of androgens on cancellous bone result from AR-signaling in osteoblasts - not on osteoclasts or via aromatization. The effects of androgens on cortical bone mass, on the other hand, do not require AR or ERα signaling in any cell type across the osteoblast or osteoclast differentiation lineage. Therefore, androgens must exert their effects indirectly by actions on some other cell type(s) or tissue(s). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Stavros C Manolagas · Henry M Kronenberg
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    ABSTRACT: The biomedical research enterprise - and the public support for it - is predicated on the belief that discoveries and the conclusions drawn from them can be trusted to build a body of knowledge that will be used to improve human health. As in all other areas of scientific inquiry, knowledge and understanding grow by layering new discoveries upon earlier ones. The process self-corrects and distills knowledge by discarding false ideas and unsubstantiated claims. While self-correction is inexorable in the long-term, in recent years biomedical scientists and the public alike have become alarmed and deeply troubled by the fact that many published results cannot be reproduced. The chorus of concern reached a high pitch with a recent commentary from the NIH Director, Francis S. Collins, and Principal Deputy Director, Lawrence A. Tabak, and their announcement of specific plans to enhance reproducibility of preclinical research that relies on animal models. In this invited perspective, we highlight the magnitude of the problem across biomedical fields and address the relevance of these concerns to the field of bone and mineral metabolism. We also suggest how our specialty journals, our scientific organizations, and our community of bone and mineral researchers can help to overcome this troubling trend. © 2014 American Society for Bone and Mineral Research.
    No preview · Article · Oct 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    ABSTRACT: A decline of the levels and activity of Sirtuin1 (Sirt1), a NAD+ class III histone deacetylase, with age contributes to the development of several diseases including type 2 diabetes, neurodegeneration, inflammation, and cancer. The anti-aging effects of Sirt1 evidently result from the deacetylation of many transcription factors and co-factors including members of the Forkhead box O (FoxO) family and β-catenin. Wnt/β-catenin is indispensable for osteoblast generation. FoxOs, on the other hand, sequester β-catenin and inhibit osteoprogenitor proliferation. Here, we have deleted Sirt1 in osteoprogenitors expressing Osterix1 (Osx1)-Cre and their descendants. Sirt1ΔOsx1 mice had lower cortical thickness in femora and vertebrae because of reduced bone formation at the endocortical surface. In line with this, osteoprogenitor cell cultures from the Sirt1ΔOsx1 mice exhibited lower alkaline phosphatase activity and mineralization, as well as decreased proliferation and increased apoptosis. These changes were associated with decreased Wnt/β-catenin signaling and expression of cyclin D1 and resulted from increased binding of FoxOs to β-catenin. These findings demonstrate that Sirt1-induced deacetylation of FoxOs unleashes Wnt signaling. A decline in Sirt1 activity in osteoblast progenitors with aging may, therefore, contribute to the age-related loss of bone mass. Together with evidence that Sirt1 activators increase bone mass in aged mice, our results also suggest that Sirt1 could be a therapeutic target for osteoporosis.
    Full-text · Article · Jul 2014 · Journal of Biological Chemistry
  • Stavros C. Manolagas
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    ABSTRACT: Major advances in understanding basic bone biology and the cellular and molecular mechanisms responsible for the development of osteoporosis, over the last 20 years, have dramatically altered the management of this disease. The purpose of this mini-review is to highlight the seminal role of Wnt signaling in bone homeostasis and disease and the emergence of novel osteoporosis therapies by targeting Wnt signaling with drugs.
    No preview · Article · Jul 2014 · Maturitas
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    ABSTRACT: Parathyroid hormone (PTH) excess stimulates bone resorption. This effect is associated with increased expression of the osteoclastogenic cytokine receptor activator of nuclear factor кB ligand (RANKL) in bone. However, several different cell types, including bone marrow stromal cells, osteocytes, and T lymphocytes, express both RANKL and the PTH receptor and it is unclear whether RANKL expression by any of these cell types is required for PTH-induced bone loss. Here we have used mice lacking the RANKL gene in osteocytes to determine whether RANKL produced by this cell type is required for the bone loss caused by secondary hyperparathyroidism induced by dietary calcium deficiency in adult mice. Thirty days of dietary calcium deficiency caused bone loss in control mice, but this effect was blunted in mice lacking RANKL in osteocytes. The increase in RANKL expression in bone and the increase in osteoclast number caused by dietary calcium deficiency were also blunted in mice lacking RANKL in osteocytes. These results demonstrate that RANKL produced by osteocytes contributes to the increased bone resorption and the bone loss caused by secondary hyperparathyroidism, strengthening the evidence that osteocytes are an important target cell for hormonal control of bone remodeling.
    No preview · Article · Jun 2014 · Bone
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    ABSTRACT: Besides their cell-damaging effects in the setting of oxidative stress, reactive oxygen species (ROS) play an important role in physiological intracellular signalling by triggering proliferation and survival. FoxO transcription factors counteract ROS generation by upregulating antioxidant enzymes. Here we show that intracellular H2O2 accumulation is a critical and purposeful adaptation for the differentiation and survival of osteoclasts, the bone cells responsible for the resorption of mineralized bone matrix. Using mice with conditional loss or gain of FoxO transcription factor function, or mitochondria-targeted catalase in osteoclasts, we demonstrate this is achieved, at least in part, by downregulating the H2O2-inactivating enzyme catalase. Catalase downregulation results from the repression of the transcriptional activity of FoxO1, 3 and 4 by RANKL, the indispensable signal for the generation of osteoclasts, via an Akt-mediated mechanism. Notably, mitochondria-targeted catalase prevented the loss of bone caused by loss of oestrogens, suggesting that decreasing H2O2 production in mitochondria may represent a rational pharmacotherapeutic approach to diseases with increased bone resorption.
    Full-text · Article · Apr 2014 · Nature Communications

  • No preview · Conference Paper · Feb 2014

  • No preview · Conference Paper · Feb 2014
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    ABSTRACT: Skeletal aging is accompanied by decreased cancellous bone mass and increased formation of pores within cortical bone. The latter accounts for a large portion of the increase in non-vertebral fractures after age 65 in humans. We selectively deleted Bak and Bax, two genes essential for apoptosis, in two types of terminally differentiated bone cells: the short-lived osteoblasts that elaborate the bone matrix, and the long-lived osteocytes that are immured within the mineralized matrix and choreograph the regeneration of bone. Attenuation of apoptosis in osteoblasts increased their working lifespan and thereby cancellous bone mass in the femur. In long-lived osteocytes, however, it caused dysfunction with advancing age and greatly magnified intracortical femoral porosity associated with increased production of receptor activator of nuclear factor-κB ligand and vascular endothelial growth factor. Increasing bone mass by artificial prolongation of the inherent lifespan of short-lived osteoblasts, while exaggerating the adverse effects of aging on long-lived osteocytes, highlights the seminal role of cell age in bone homeostasis. In addition, our findings suggest that distress signals produced by old and/or dysfunctional osteocytes are the culprits of the increased intracortical porosity in old age.
    Preview · Article · Jan 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research

  • No preview · Article · Dec 2013
  • Stavros C Manolagas · Charles A O'Brien · Maria Almeida
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    ABSTRACT: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.
    No preview · Article · Sep 2013 · Nature Reviews Endocrinology
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    Jian Zhou · Shiqiao Ye · Toshifumi Fujiwara · Stavros C Manolagas · Haibo Zhao
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    ABSTRACT: Iron is essential for osteoclast differentiation, and iron overload in a variety of hematologic diseases is associated with excessive bone resorption. Iron uptake by osteoclast precursors via the transferrin cycle increases mitochondrial biogenesis, reactive oxygen species production, and activation of cAMP response element-binding protein, a critical transcription factor downstream of receptor activator of NF-κB-ligand-induced calcium signaling. These changes are required for the differentiation of osteoclast precursors to mature bone-resorbing osteoclasts. However, the molecular mechanisms regulating cellular iron metabolism in osteoclasts remain largely unknown. In this report, we provide evidence that Steap4, a member of the six-transmembrane epithelial antigen of prostate (Steap) family proteins, is an endosomal ferrireductase with a critical role in cellular iron utilization in osteoclasts. Specifically, we show that Steap4 is the only Steap family protein that is up-regulated during osteoclast differentiation. Knocking down Steap4 expression in vitro by lentivirus-mediated short hairpin RNAs inhibits osteoclast formation and decreases cellular ferrous iron, reactive oxygen species, and the activation of cAMP response element-binding protein. These results demonstrate that Steap4 is a critical enzyme for cellular iron uptake and utilization in osteoclasts and, thus, indispensable for osteoclast development and function.
    Full-text · Article · Aug 2013 · Journal of Biological Chemistry
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    Stavros C Manolagas · Steven R Cummings

    Preview · Article · Aug 2013 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
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    ABSTRACT: Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activates members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis.
    Preview · Article · Jul 2013 · The Journal of clinical investigation
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    Full-text · Article · May 2013 · Journal of Bone and Mineral Research

Publication Stats

25k Citations
1,808.52 Total Impact Points


  • 2000-2015
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
  • 1995-2015
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 1995-2011
    • University of Arkansas for Medical Sciences
      • • Center for Osteoporosis and Metabolic Bone Diseases
      • • Division of Endocrinology and Metabolism
      • • Department of Geriatrics
      Little Rock, Arkansas, United States
  • 1993-2009
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1980-2006
    • University of California, San Diego
      • • Department of Medicine
      • • Division of Endocrinology & Metabolism
      San Diego, California, United States
  • 1999
    • Yale University
      • Section of Endocrinology & Metabolism
      New Haven, Connecticut, United States
  • 1989-1994
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, Indiana, United States
  • 1992
    • Indiana University School of Medicine
      Indianapolis, Indiana, United States
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 1983
    • Naval Medical Center San Diego
      San Diego, California, United States
    • Stanford Medicine
      Stanford, California, United States
  • 1979
    • The University of Manchester
      • School of Biomedicine
      Manchester, England, United Kingdom