47 results on '"Koh, Amy J."'
Search Results
2. Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model
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Koh, Amy J, Nam, Hwa Kyung, Michalski, Megan N, Do, Justin, McCauley, Laurie K, and Hatch, Nan E
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- 2022
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3. Caspase-9 driven murine model of selective cell apoptosis and efferocytosis
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Batoon, Lena, Koh, Amy J., Kannan, Rahasudha, McCauley, Laurie K., and Roca, Hernan
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- 2023
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4. Local pulsatile PTH delivery regenerates bone defects via enhanced bone remodeling in a cell-free scaffold
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Dang, Ming, Koh, Amy J., Jin, Xiaobing, McCauley, Laurie K., and Ma, Peter X.
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- 2017
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5. The effects of preosteoblast‐derived exosomes on macrophages and bone in mice.
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Hakki, Sema S., Batoon, Lena, Koh, Amy J., Kannan, Rahasudha, Mendoza‐Reinoso, Veronica, Rubin, John, Mccauley, Laurie K., and Roca, Hernan
- Subjects
EXOSOMES ,BONE density ,MACROPHAGES ,WESTERN immunoblotting ,COMPACT bone ,BONE marrow ,OSTEOBLASTS - Abstract
The effect of preosteoblast‐derived exosomes on bone marrow macrophages (BMMΦ) and calvarial osteoblasts (cOB) was evaluated in vitro, and bone formation studies were performed in vivo in mice. Preosteoblastic MC3T3‐E1 clone 4 (MC4) cell‐derived exosomes (MC4exo) were characterized with particle tracking, transmission electron microscopy and western blot analysis to validate size, number, shape and phenotypic exosome markers. Exosomes pre‐labelled with PKH67 were incubated with BMMΦ and phagocytosis of exosomes was confirmed. To examine the effect of MC4exo on macrophage polarization, BMMΦ were treated with MC4exo and the expression of pro‐ and anti‐inflammatory cytokines was determined by qPCR. MC4exo treatment upregulated mRNA expression of Cd86, Il1β, Ccl2, Rankl and Nos, and downregulated Cd206, Il10 and Tnfα, suggesting a shift towards pro‐inflammatory 'M1‐like' macrophage polarization. Combination of RANKL and MC4exo increased osteoclast differentiation of BMMΦ in comparison to RANKL alone as analysed by TRAP staining. MC4exo treatment showed no significant effect on calvarial osteoblast mineralization. For in vivo studies, intratibial inoculation of MC4exo (2 × 109 particles in PBS, n = 12) and vehicle control (PBS only, n = 12) was performed in C57Bl/6 mice (8 weeks, male). Micro‐CT analyses of the trabecular and cortical bone compartments were assessed at 4 weeks post‐injection. Tibial sections were stained for TRAP activity to determine osteoclast presence and immunofluorescence staining was performed to detect osteocalcin (Ocn), osterix (Osx) and F4/80 expression. Intratibial inoculation of MC4exo increased the diaphyseal bone mineral density and trabecular bone volume fraction due to increased trabecular number. This increase in bone was accompanied by a reduction in bone marrow macrophages and osteoclasts at the experimental endpoint. Together, these findings suggest that preosteoblast‐derived exosomes enhanced bone formation by influencing macrophage responses. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone
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Roca, Hernan, Jones, Jacqueline D., Purica, Marta C., Weidner, Savannah, Koh, Amy J., Kuo, Robert, Wilkinson, John E., Wang, Yugang, Daignault-Newton, Stephanie, Pienta, Kenneth J., Morgan, Todd M., Keller, Evan T., Nor, Jacques E., Shea, Lonnie D., and McCauley, Laurie K.
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Apoptosis -- Analysis ,Macrophages -- Growth -- Analysis ,Cytokines -- Growth -- Analysis ,Inflammation -- Development and progression -- Analysis ,Prostate cancer -- Development and progression -- Analysis ,Cancer metastasis -- Development and progression -- Analysis ,Health care industry - Abstract
During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-[kappa]B(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5 -mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics., Introduction The most common site of prostate cancer metastasis is bone, with an incidence of 65%-80% in patients with advanced disease (1). Once cancer cells spread to bone, they significantly [...]
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- 2018
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7. Preprogrammed Long‐Term Systemic Pulsatile Delivery of Parathyroid Hormone to Strengthen Bone
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Dang, Ming, Koh, Amy J., Danciu, Theodora, McCauley, Laurie K., and Ma, Peter X.
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- 2017
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8. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone
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Cho, Sun Wook, Soki, Fabiana N., Koh, Amy J., Eber, Matthew R., Entezami, Payam, In Park, Serk, van Rooijen, Nico, and McCauley, Laurie K.
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- 2014
9. Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone
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Li, Xin, Liao, Jinhui, Park, Serk In, Koh, Amy J., Sadler, William D., Pienta, Kenneth J., Rosol, Thomas J., and McCauley, Laurie K.
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- 2011
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10. Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells
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Novince, Chad M., Koh, Amy J., Michalski, Megan N., Marchesan, Julie T., Wang, Jason, Jung, Younghun, Berry, Janice E., Eber, Matthew R., Rosol, Thomas J., Taichman, Russell S., and McCauley, Laurie K.
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- 2011
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11. Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation
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Pettway, Glenda J., Meganck, Jeffrey A., Koh, Amy J., Keller, Evan T., Goldstein, Steven A., and McCauley, Laurie K.
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- 2008
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12. Impact of Proteoglycan-4 and Parathyroid Hormone on Articular Cartilage
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Novince, Chad M., Entezami, Payam, Wilson, Christopher G., Wang, Jason, Oh, Seo, Koh, Amy J., Michalski, Megan N., Sinder, Benjamin P., Kozloff, Kenneth M., Taichman, Russell S., and McCauley, Laurie K.
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- 2013
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13. Cells of the Osteoclast Lineage as Mediators of the Anabolic Actions of Parathyroid Hormone in Bone
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Koh, Amy J., Demiralp, Burak, Neiva, Kathleen G., Hooten, Joanna, Nohutcu, Rahime M., Shim, Hyunsuk, Datta, Nabanita S., Taichman, Russell S., and McCauley, Laurie K.
- Published
- 2005
14. Anabolic actions of PTH in murine models: two decades of insights.
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Zweifler, Laura E., Koh, Amy J., Daignault‐Newton, Stephanie, and McCauley, Laurie K.
- Abstract
Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N‐terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild‐type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5–6 weeks, and a PTH dose of 30–60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1‐α‐hydroxylase (Pth;1α(OH)ase, 62‐fold), amphiregulin (Areg, 15.8‐fold), and PTH related protein (Pthrp, 10.2‐fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, −9.7‐fold), low‐density lipoprotein receptor‐related protein 6 (Lrp6, 1.3‐fold), and low‐density lipoprotein receptor‐related protein 5 (Lrp5, −1.0‐fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]
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- 2021
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15. Anabolic Actions of Parathyroid Hormone during Bone Growth Are Dependent on c-fos
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Demiralp, Burak, Chen, Hen-Li, Koh, Amy J., Keller, Evan T., and McCauley, Laurie K.
- Published
- 2002
16. 3′,5′-Cyclic Adenosine Monophosphate Activation in Osteoblastic Cells: Effects on Parathyroid Hormone-1 Receptors and Osteoblastic Differentiation in Vitro*
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Koh, Amy J, Beecher, Christopher A, Rosol, Thomas J, and McCauley, Laurie K
- Published
- 1999
17. Bone Mass is Compromised by the Chemotherapeutic Trabectedin in Association with Effects on Osteoblasts and Macrophage Efferocytosis
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Sinder, Benjamin P., Zweifler, Laura, Koh, Amy J., Michalski, Megan N., Hofbauer, Lorenz C., Aguirre, Jose Ignacio, Roca, Hernan, and McCauley, Laurie K.
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Male ,Osteoblasts ,Macrophages ,Osteoclasts ,Dioxoles ,Organ Size ,Article ,Bone and Bones ,Mice, Inbred C57BL ,Calcification, Physiologic ,Gene Expression Regulation ,Phagocytosis ,Osteogenesis ,Parathyroid Hormone ,Tetrahydroisoquinolines ,Cancellous Bone ,Cortical Bone ,Animals ,Trabectedin - Abstract
Macrophages have established roles supporting bone formation. Despite their professional phagocytic nature, the role of macrophage phagocytosis in bone homeostasis is not well understood. Interestingly, apoptosis is a pivotal feature of cellular regulation and the primary fate of osteoblasts is apoptosis. Efferocytosis (phagocytosis of apoptotic cells) is a key physiologic process for the homeostasis of many tissues, and is associated with expression of osteoinductive factors. To test effects of macrophage depletion and compromised phagocytosis on bone, 16-week-old male C57BL/6J mice were treated with trabectedin-a chemotherapeutic with established anti-macrophage effects. Trabectedin treatment reduced F4/80+ and CD68+ macrophages in the bone marrow as assessed by flow cytometry, osteal macrophages near the bone surface, and macrophage viability in vitro. Trabectedin treatment significantly reduced marrow gene expression of key phagocytic factors (Mfge8, Mrc1), and macrophages from treated mice had a reduced ability to phagocytose apoptotic mimicry beads. Macrophages cultured in vitro and treated with trabectedin displayed reduced efferocytosis of apoptotic osteoblasts. Moreover, efferocytosis increased macrophage osteoinductive TGF-β production and this increase was inhibited by trabectedin. Long-term (6-week) treatment of 16-week-old C57BL/6J mice with trabectedin significantly reduced trabecular BV/TV and cortical BMD. Although trabectedin reduced osteoclast numbers in vitro, osteoclast surface in vivo was not altered. Trabectedin treatment reduced serum P1NP as well as MS/BS and BFR/BS, and inhibited mineralization and Runx2 gene expression of osteoblast cultures. Finally, intermittent PTH 1-34 (iPTH) treatment was administered in combination with trabectedin, and iPTH increased trabecular bone volume fraction (BV/TV) in trabectedin-treated mice. Collectively, the data support a model whereby trabectedin significantly reduces bone mass due to compromised macrophages and efferocytosis, but also due to direct effects on osteoblasts. This data has immediate clinical relevance in light of increasing use of trabectedin in oncology. © 2017 American Society for Bone and Mineral Research.
- Published
- 2017
18. Parathyroid hormone (PTH) facilitates macrophage efferocytosis in bone marrow via pro-resolving mediators Resolvin D1 and Resolvin D2
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McCauley, Laurie K., Dalli, Jesmond, Koh, Amy J., Chiang, Nan, and Serhan, Charles N.
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Male ,Mice ,Docosahexaenoic Acids ,Phagocytosis ,Bone Marrow ,Parathyroid Hormone ,Macrophages ,Animals ,Humans ,Article ,Cells, Cultured - Abstract
Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by as yet poorly defined mechanisms. Specialized pro-resolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution but little is known regarding this process in the bone marrow. In the present report, metabololipidomic profiling via liquid chromatographic mass spectrometry revealed higher levels of specialized pro-resolving mediators (SPM) in the bone marrow relative to the spleen. The endocrine and bone anabolic agent parathyroid hormone (PTH) increased SPM levels including resolvins (Rv) in bone marrow. Human and murine primary macrophages efferocytosed apoptotic osteoblasts in vitro, and resolvin (Rv) D1 and RvD2 (10 pM-10 nM) enhanced this process. These findings support a unique profile of specialized lipid mediators in bone marrow that contributes to a feedback system for resolution of inflammation and maintenance of skeletal homeostasis.
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- 2014
19. Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide.
- Author
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Michalski, Megan N., Seydel, Anna L., Siismets, Erica M., Zweifler, Laura E., Koh, Amy J., Sinder, Benjamin P., Aguirre, J. Ignacio, Atabai, Kamran, Roca, Hernan, and McCauley, Laurie K.
- Published
- 2018
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20. Bone Mass Is Compromised by the Chemotherapeutic Trabectedin in Association With Effects on Osteoblasts and Macrophage Efferocytosis.
- Author
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Sinder, Benjamin P, Zweifler, Laura, Koh, Amy J, Michalski, Megan N, Hofbauer, Lorenz C, Aguirre, Jose Ignacio, Roca, Hernan, and McCauley, Laurie K
- Abstract
ABSTRACT Macrophages have established roles supporting bone formation. Despite their professional phagocytic nature, the role of macrophage phagocytosis in bone homeostasis is not well understood. Interestingly, apoptosis is a pivotal feature of cellular regulation and the primary fate of osteoblasts is apoptosis. Efferocytosis (phagocytosis of apoptotic cells) is a key physiologic process for the homeostasis of many tissues, and is associated with expression of osteoinductive factors. To test effects of macrophage depletion and compromised phagocytosis on bone, 16-week-old male C57BL/6J mice were treated with trabectedin-a chemotherapeutic with established anti-macrophage effects. Trabectedin treatment reduced F4/80+ and CD68+ macrophages in the bone marrow as assessed by flow cytometry, osteal macrophages near the bone surface, and macrophage viability in vitro. Trabectedin treatment significantly reduced marrow gene expression of key phagocytic factors ( Mfge8, Mrc1), and macrophages from treated mice had a reduced ability to phagocytose apoptotic mimicry beads. Macrophages cultured in vitro and treated with trabectedin displayed reduced efferocytosis of apoptotic osteoblasts. Moreover, efferocytosis increased macrophage osteoinductive TGF-β production and this increase was inhibited by trabectedin. Long-term (6-week) treatment of 16-week-old C57BL/6J mice with trabectedin significantly reduced trabecular BV/TV and cortical BMD. Although trabectedin reduced osteoclast numbers in vitro, osteoclast surface in vivo was not altered. Trabectedin treatment reduced serum P1NP as well as MS/BS and BFR/BS, and inhibited mineralization and Runx2 gene expression of osteoblast cultures. Finally, intermittent PTH 1-34 (iPTH) treatment was administered in combination with trabectedin, and iPTH increased trabecular bone volume fraction (BV/TV) in trabectedin-treated mice. Collectively, the data support a model whereby trabectedin significantly reduces bone mass due to compromised macrophages and efferocytosis, but also due to direct effects on osteoblasts. This data has immediate clinical relevance in light of increasing use of trabectedin in oncology. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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21. Modulation of Osteoblastic Cell Efferocytosis by Bone Marrow Macrophages.
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Michalski, Megan N., Koh, Amy J., Weidner, Savannah, Roca, Hernan, and McCauley, Laurie K.
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- 2016
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22. Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone.
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Al‐Dujaili, Saja A., Koh, Amy J., Dang, Ming, Mi, Xue, Chang, Wenhan, Ma, Peter X., and McCauley, Laurie K.
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- 2016
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23. Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis.
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Soki, Fabiana N., Koh, Amy J., Jones, Jacqueline D., Yeo Won Kim, Jinlu Dai, Keller, Evan T., Pienta, Kenneth J., Atabai, Kamran, Roca, Hernan, and McCauley, Laurie K.
- Subjects
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MACROPHAGES , *MILKFAT , *EPIDERMAL growth factor receptors regulation , *PROTEIN-tyrosine kinase regulation , *DISEASE progression , *PROSTATE cancer & genetics , *DISEASES - Abstract
Tumor cells secrete factors that modulate macrophage activation and polarization into M2 type tumor-associated macrophages, which promote tumor growth, progression, and metastasis. The mechanisms that mediate this polarization are not clear. Macrophages are phagocytic cells that participate in the clearance of apoptotic cells, a process known as efferocytosis. Milk fat globule- EGF factor 8 (MFG-E8) is a bridge protein that facilitates efferocytosis and is associated with suppression of proinflammatory responses. This study investigated the hypothesis that MFG-E8-mediated efferocytosis promotes M2 polarization. Tissue and serum exosomes from prostate cancer patients presented higher levels of MFG-E8 compared with controls, a novel finding in human prostate cancer. Coculture of macrophages with apoptotic cancer cells increased efferocytosis, elevated MFG-E8 protein expression levels, and induced macrophage polarization into an alternatively activated M2 phenotype. Administration of antibody against MFG-E8 significantly attenuated the increase in M2 polarization. Inhibition of STAT3 phosphorylation using the inhibitor Stattic decreased efferocytosis and M2 macrophage polarization in vitro, with a correlating increase in SOCS3 protein expression. Moreover, MFG-E8 knockdown tumor cells cultured with wild-type or MFG-E8-deficient macrophages resulted in increased SOCS3 expression with decreased STAT3 activation. This suggests that SOCS3and phospho-STAT3 act in an inversely dependent manner when stimulated by MFG-E8 and efferocytosis. These results uncover a unique role of efferocytosis via MFG-E8 as a mechanism for macrophage polarization into tumor-promoting M2 cells. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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24. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.
- Author
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Sun Wook Cho, Soki, Fabiana N., Koh, Amy J., Eber, Matthew R., Entezami, Payam, Serk In Park, van Rooijen, Nico, and McCauley, Laurie K.
- Subjects
MACROPHAGES ,BONE remodeling ,PARATHYROID hormone ,BONE marrow ,HOMEOSTASIS ,ABLATION techniques ,LIPOSOMES ,BONE growth - Abstract
Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms
+ myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68+ cells, whereas clodronate liposome-treated mice had increased CD68+ and CD163+ cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis. [ABSTRACT FROM AUTHOR]- Published
- 2014
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25. Proteoglycan 4: A dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism.
- Author
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Novince, Chad M, Michalski, Megan N, Koh, Amy J, Sinder, Benjamin P, Entezami, Payam, Eber, Matthew R, Pettway, Glenda J, Rosol, Thomas J, Wronski, Thomas J, Kozloff, Ken M, and McCauley, Laurie K
- Abstract
Proteoglycan 4 ( Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure. © 2012 American Society for Bone and Mineral Research [ABSTRACT FROM AUTHOR]
- Published
- 2012
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26. Inhibitory Effects of Megakaryocytic Cells in Prostate Cancer Skeletal Metastasis.
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Xin Li, Koh, Amy J., Zhengyan Wang, Soki, Fabiana N., Serk In Park, Pienta, Kenneth J., and McCauley, Laurie K.
- Abstract
The article examines the inhibitory effects of megakaryotic cells in prostate cancer (PC) skeletal metastasis. Gene expression analysis showed reduced messenger ribonucleic acid (mRNA) levels for cyclin D1, and increased mRNA levels of apoptosis-associated speck-like protein containing a caspase recruitment domain and death-associated protein kinase 1 in PC-3 cells after coculture with K562 cells. Skeletal lesion development declined with the expansion of megakaryocytes in the marrow via recombinant thrombopoietin after intracardiac tumor inoculation.
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- 2011
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27. Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin-6.
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Pirih, Flavia Q., Michalski, Megan N., Cho, Sun W., Koh, Amy J., Berry, Janice E., Ghaname, Eduardo, Kamarajan, Pachiyappan, Bonnelye, Edith, Ross, Charles W., Kapila, Yvonne L., Jurdic, Pierre, and McCauley, Laurie K.
- Subjects
PARATHYROID hormone ,HEMATOPOIESIS ,BIOCHEMICAL mechanism of action ,INTERLEUKINS ,BONE marrow ,PROTEIN-tyrosine kinases ,APOPTOSIS ,CARCINOGENESIS ,ANIMAL models in research - Abstract
Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45
+ and CD11b+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin- Sca-1+ c-Kit+ (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion. [ABSTRACT FROM AUTHOR]- Published
- 2010
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28. Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions.
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Liao, Jinhui, Li, Xin, Koh, Amy J., Berry, Janice E., Thudi, Nanda, Rosol, Thomas J., Pienta, Kenneth J., and McCauley, Laurie K.
- Abstract
Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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29. Cyclin D1 as a Target for the Proliferative Effects of PTH and PTHrP in Early Osteoblastic Cells.
- Author
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Datta, Nabanita S., Pettway, Glenda J., Chen Chen, Koh, Amy J., and McCauley, Laurie K.
- Abstract
The article presents a study on the action of PTH or PTHrP on the cell cycle during osteoblast proliferation. The materials and methods used in the study is presented. The results of the study are discussed. In conclusion, data shows that PTH and PTHrP induce cyclin D1 expression in early osteoblastic cells.
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- 2007
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30. The role of parathyroid hormone-related protein in the regulation of osteoclastogenesis by cementoblasts.
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Boabaid, Fernanda, Berry, Janice E., Koh, Amy J., Somerman, Martha J., McCauley, Laurie K., and McCcauley, Laurie K
- Subjects
PARATHYROID hormone-related protein ,OSTEOCLASTS ,LIGANDS (Biochemistry) ,NF-kappa B ,DENTAL cements - Abstract
Background: Parathyroid hormone-related protein (PTHrP) promotes osteoclastogenesis by inhibiting expression of osteoprotegerin (OPG), a decoy receptor for the receptor activator of nuclear factor kappa B (RANK), and by enhancing production of RANK ligand (RANKL) by osteoblasts. However, little is known regarding the role of PTHrP in regulating cementoblast-mediated osteoclastogenesis.Methods: This study determined the impact of PTHrP on osteoclastogenesis using: 1) OCCM-30 (immortalized murine cementoblasts), 2) RAW 264.7 cells (murine myeloid cells), or 3) OCCM-30 plus RAW 264.7 cells. Cells were treated with PTHrP (1-34), RANKL, or PTHrP and RANKL combined. Enzyme-linked immunosorbent assays (ELISAs) for OPG and RANKL were performed on media and cell lysates, and tartrate-resistant acid phosphatase (TRAP) and mRNA detection for the osteoclast associated receptor (OSCAR) were performed.Results: The highest numbers of TRAP-positive cells and cells expressing OSCAR were found in the RAW cell group treated with either RANKL alone or RANKL and PTHrP. TRAP-positive cells were fewer when OCCM cells were co-cultured with RAW, but the greatest numbers were still with both PTHrP and RANKL. OPG levels were highest from OCCM cells and PTHrP decreased these levels. In contrast, RANKL levels were low in OCCM cell lysates and PTHrP increased RANKL. In vivo studies also revealed high osteoclastic activity surrounding developing teeth in mice administered PTH.Conclusions: These results demonstrate that PTHrP influences the balance of OPG and RANKL production by cementoblasts, and further indicate that this effect, in the context of surrounding cells, might have a significant impact on osteoclastogenesis, root resorption, and tooth eruption. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
31. Impact of the Mitogen-activated Protein Kinase Pathway on Parathyroid Hormone-related Protein Actions in Osteoblasts.
- Author
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Chen Chen, Koh, Amy J., Datta, Nabanita S., Jian Zhang, Keller, Evan T., Guozhi Xiao, Franceschi, Renny T., D'Silva, Nisha J., and McCauley, Laurie K.
- Subjects
- *
PROTEIN kinases , *MITOGENS , *PARATHYROID hormone , *CYCLIC adenylic acid , *GENE expression , *MESSENGER RNA - Abstract
Parathyroid hormone-related protein (PTHrP) regulates proliferation and differentiation of osteoblastic cells via binding to the parathyroid hormone receptor (PTH-1R). The cAMP-dependent protein kinase A pathway governs the majority of these effects, but recent evidence also implicates the MAPK pathway. MC3T3-E1 subclone 4 cells (MC4) were treated with the MAPK inhibitor U0126 and PTHrP. In differentiated MC4 cells, osteocalcin and bone sialoprotein gene expression were both down-regulated by PTHrP and also by inhibition of the MAPK pathway. PTHrP-mediated down-regulation of PTH-1R mRNA and up-regulation of c-fos mRNA were MAPK-independent, whereas PTHrP stimulation of fra-2 and interleukin-6 (IL-6) mRNA was MAPK-dependent. Luciferase promoter assays revealed that regulation of IL-6 involved the cAMP-dependent protein kinase A and MAPK pathways with a potential minor role of the protein kinase C pathway, and a promoter region containing an activator protein-1 site was necessary for PTHrP-induced IL-6 gene transcription. An alternative pathway, through cAMP/Epac/Rap1/MAPK, mediated ERK phosphorylation but was not sufficient for IL-6 promoter activation. Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity. Most interesting, a bidirectional effect was found with PTHrP increasing phosphorylated ERK in undifferentiated MC4 cells but decreasing phosphorylated ERK in differentiated cells. These data indicate that inactivation of the MAPK pathway shows differential regulation of PTHrP-stimulated activator protein-1 members, blocks PTHrPstimulated IL-6, and synergistically down-regulates certain osteoblastic markers associated with differentiation. These novel findings indicate that the MAPK pathway plays a selective but important role in the actions of PTHrP. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
32. PTH/PTHrP receptor is temporally regulated during osteoblast differentiation and is associated with collagen synthesis.
- Author
-
McCauley, Laurie K., Koh, Amy J., Beecher, Christopher A., Cui, Yingqi, Rosol, Thomas J., and Franceschi, Renny T.
- Published
- 1996
- Full Text
- View/download PDF
33. Effects of differentiation and transforming growth factor β1 on PTH/PTHrP receptor mRNA levels in MC3T3-E1 cells.
- Author
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Mccauley, Laurie K., Koh, Amy J., Beecher, Christopher A., Cui, Yingqi, Decker, James D., and Franceschi, Renny T.
- Published
- 1995
- Full Text
- View/download PDF
34. Expression of Extracellular Matrix Proteins in Human Periodontal Ligament Cells During Mineralization In Vitro.
- Author
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Nohutcu, Rahime M., McCauley, Laurie K., Koh, Amy J., and Somerman, Martha J.
- Published
- 1997
- Full Text
- View/download PDF
35. Unique Pro-Inflammatory Response of Macrophages during Apoptotic Cancer Cell Clearance.
- Author
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Mendoza-Reinoso, Veronica, Baek, Dah Youn, Kurutz, Adrianne, Rubin, John R., Koh, Amy J., McCauley, Laurie K., and Roca, Hernan
- Subjects
CANCER cells ,MACROPHAGES ,PERITONEAL macrophages ,BONE marrow ,BONE growth ,BONE cells ,GENE expression profiling - Abstract
The clearance of apoptotic cells by macrophages (efferocytosis) is crucial to maintain normal tissue homeostasis; however, efferocytosis of cancer cells frequently results in inflammation and immunosuppression. Recently, we demonstrated that efferocytosis of apoptotic prostate cancer cells by bone marrow-derived macrophages induced a pro-inflammatory response that accelerated metastatic tumor growth in bone. To evaluate the microenvironmental impact of macrophages and their efferocytic function, we compared peritoneal macrophages (P-MΦ) versus bone marrow-derived macrophages (BM-MΦs) using an efferocytosis in vitro model. The capability to engulf apoptotic prostate cells was similar in BM-MΦs and P-MΦs. Ex vivo analysis of BM-MΦs showed an M2-like phenotype compared with a predominantly M1-like phenotype in P-MΦs. A distinct gene and protein expression profile of pro-inflammatory cytokines was found in BM-MΦs as compared with P-MΦs engulfing apoptotic prostate cancer cells. Importantly, the reprogramming of BM-MΦs toward an M1-like phenotype mitigated their inflammatory cytokine expression profile. In conclusion, BM-MΦs and P-MΦs are both capable of efferocytosing apoptotic prostate cancer cells; however, BM-MΦs exert increased inflammatory cytokine expression that is dependent upon the M2 polarization stage of macrophages. These findings suggest that bone marrow macrophage efferocytosis of apoptotic cancer cells maintains a unique pro-inflammatory microenvironment that may support a fertile niche for cancer growth. Finally, bone marrow macrophage reprogramming towards M1-type by interferon-γ (IFN-γ) induced a significant reduction in the efferocytosis-mediated pro-inflammatory signature. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
36. Cover Image, Volume 117, Number 7, July 2016.
- Author
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Al‐Dujaili, Saja A., Koh, Amy J., Dang, Ming, Mi, Xue, Chang, Wenhan, Ma, Peter X., and McCauley, Laurie K.
- Published
- 2016
- Full Text
- View/download PDF
37. Cutting Edge: Parathyroid Hormone Facilitates Macrophage Efferocytosis in Bone Marrow via Proresolving Mediators Resolvin D1 and Resolvin D2.
- Author
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McCauley, Laurie K., Dalli, Jesmond, Koh, Amy J., Nan Chiang, and Serhan, Charles N.
- Subjects
- *
PARATHYROID hormone regulation , *MACROPHAGES , *BONE marrow physiology , *IMMUNE system , *PHYSIOLOGY ,BONE marrow examination - Abstract
Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by poorly defined mechanisms. Specialized proresolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution, but little is known regarding this process in the bone marrow. In this study, metabololipidomic profiling via liquid chromatography mass spectrometry revealed higher levels of specialized proresolving mediators in the bone marrow relative to the spleen. The endocrine and bone anabolic agent parathyroid hormone increased specialized proresolving mediator levels, including resolvins (Rvs), in bone marrow. Human and murine primary macrophages efferocytosed apoptotic osteoblasts in vitro, and RvD1 and RvD2 (10 pM-10 nM) enhanced this process. These findings support a unique profile of specialized lipid mediators in bone marrow that contribute to a feedback system for resolution of inflammation and maintenance of skeletal homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
38. The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone.
- Author
-
Sun Wook Cho, Pirih, Flavia Q., Koh, Amy J., Michalski, Megan, Eber, Matthew R., Ritchie, Kathryn, Sinder, Benjamin, Seojin Oh, Al-Dujaili, Saja A., JoonHo Lee, Kozloff, Ken, Danciu, Theodora, Wronski, Thomas J., and McCauley, Laurie K.
- Subjects
- *
PARATHYROID hormone , *INTERLEUKIN-6 , *STEM cells , *BONE marrow , *HIGHLY active antiretroviral therapy - Abstract
Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone micro environment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6+/+ and IL-6-/- mice. PTH mediated hematopoietic cell expansion was attenuated in IL-6-/- compared with IL-6+/+ bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6-/- earlier than IL-6+/+ marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6-/- marrow. In the skeletal system, although intermittent PTH administration to IL-6+/+and IL-6-/-mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. Anabolic actions of PTH (1-34): Use of a novel tissue engineering model to investigate temporal effects on bone
- Author
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Pettway, Glenda J., Schneider, Abraham, Koh, Amy J., Widjaja, Effendi, Morris, Michael D., Meganck, Jeffrey A., Goldstein, Steven A., and McCauley, Laurie K.
- Subjects
- *
PARATHYROID hormone , *OSTEOPOROSIS , *TISSUE engineering , *BONE marrow , *MESSENGER RNA - Abstract
Abstract: PTH is in clinical use for the treatment of osteoporosis and is under intensive investigation for its potential in applications of tissue engineering, fracture healing, and implant integration. However, the mechanisms of its action to stimulate bone formation are still unclear. A novel bone tissue engineering model was used to elucidate basic mechanisms of PTH anabolic actions. Ectopic ossicles containing cortical bone, trabecular bone, and a hematopoietic marrow were generated from implanted bone marrow stromal cells (BMSC). One week after implantation, nude mice were administered PTH or vehicle for 1 week (group 1), 3 weeks (group 2), or 7 weeks (group 3). Another group was also treated for 3 weeks, initiated 12 weeks after implantation (group 4). Micro-radiography and histomorphometry revealed increased marrow cellularity in group 1 PTH-treated ossicles, increased bone in group 2 PTH-treated ossicles, and similar amounts of bone in both group 3 and 4 ossicles regardless of treatment. Incidence of phosphate mineral and phosphate mineral to hydroxyproline ratio via Raman spectroscopy were significantly higher after 3 weeks versus 1 week of PTH treatment, but there was no difference between PTH- and vehicle-treated ossicles. Early events of PTH action in group 1 ossicles and the effects of a single injection of PTH on 1- and 2-week-old ossicles were evaluated by Northern blot analysis. Osteocalcin (OC) mRNA was increased after 1 week of intermittent PTH treatment in ossicles and calvaria but an acute injection did not alter OC mRNA. In contrast, a single injection of PTH increased matrix γ-carboxyglutamic acid protein (MGP) mRNA in 2-week-old ossicles. Differential and temporal-dependent effects of PTH on OC and MGP suggest at the molecular level, that PTH acts to inhibit osteoblast mineralization. However, this does not translate into tissue level alterations. These data indicate that anabolic actions of PTH in ectopic ossicles are temporally dependent on the BMSC implanted and suggest that cell implantation strategies are particularly responsive to PTH. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
40. Cyclophosphamide Creates a Receptive Microenvironment for Prostate Cancer Skeletal Metastasis.
- Author
-
Serk In Park, Jinhui Liao, Berry, Janice E., Xin Li, Koh, Amy J., Michalski, Megan E., Eber, Matthew R., Soki, Fabiana N., Sadler, David, Sud, Sudha, Tisdelle, Sandra, Daignault, Stephanie D., Nemeth, Jeffrey A., Snyder, Linda A., Wronski, Thomas J., Pienta, Kenneth J., and McCauley, Laurie K.
- Subjects
- *
PROSTATE cancer , *CYCLOPHOSPHAMIDE , *BONE marrow , *HEMATOPOIETIC system , *METASTASIS - Abstract
A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone. Priming the murine host with cyclophosphamide before intracardiac tumor cell inoculation was found to significantly promote tumor localization and subsequent growth in bone. Shortly after cyclophosphamide treatment, there was an abrupt expansion of myeloid lineage cells in the bone marrow and the peripheral blood, associated with increases in cytokines with myelogenic potential such as C-C chemokine ligand (CCL)2, interleukin (IL)-6, and VEGF-A. More importantly, neutralizing host-derived murine CCL2, but not IL-6, in the premetastatic murine host significantly reduced the prometastatic effects of cyclophosphamide. Together, our findings suggest that bone marrow perturbation by cytotoxic chemotherapy can contribute to bone metastasis via a transient increase in bone marrow myeloid cells and myelogenic cytokines. These changes can be reversed by inhibition of CCL2. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
41. Bone marrow macrophages support prostate cancer growth in bone.
- Author
-
Soki FN, Cho SW, Kim YW, Jones JD, Park SI, Koh AJ, Entezami P, Daignault-Newton S, Pienta KJ, Roca H, and McCauley LK
- Subjects
- Animals, Bone Neoplasms secondary, Bone Regeneration, Carcinogenesis, Cell Growth Processes, Cell Line, Tumor, Clodronic Acid metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Prostatic Neoplasms pathology, Receptor, Macrophage Colony-Stimulating Factor metabolism, Tumor Burden, Bone Marrow Cells immunology, Bone Neoplasms immunology, Macrophages immunology, Prostatic Neoplasms immunology
- Abstract
Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.
- Published
- 2015
- Full Text
- View/download PDF
42. Juxtacrine interaction of macrophages and bone marrow stromal cells induce interleukin-6 signals and promote cell migration.
- Author
-
Chang J, Koh AJ, Roca H, and McCauley LK
- Abstract
The bone marrow contains a heterogeneous milieu of cells, including macrophages, which are key cellular mediators for resolving infection and inflammation. Macrophages are most well known for their ability to phagocytose foreign bodies or apoptotic cells to maintain homeostasis; however, little is known about their function in the bone microenvironment. In the current study, we investigated the in vitro interaction of murine macrophages and bone marrow stromal cells (BMSCs), with focus on the juxtacrine induction of IL-6 signaling and the resultant effect on BMSC migration and growth. The juxtacrine interaction of primary mouse macrophages and BMSCs activated IL-6 signaling in the co-cultures, which subsequently enhanced BMSC migration and increased BMSC numbers. BMSCs and macrophages harvested from IL-6 knockout mice revealed that IL-6 signaling was essential for enhancement of BMSC migration and increased BMSC numbers via juxtacrine interactions. BMSCs were the main contributor of IL-6 signaling, and hence activation of the IL-6/gp130/STAT3 pathway. Meanwhile, macrophage derived IL-6 remained important for the overall production of IL-6 protein in the co-cultures. Taken together, these findings show the function of macrophages as co-inducers of migration and growth of BMSCs, which could directly influence bone formation and turnover.
- Published
- 2015
- Full Text
- View/download PDF
43. Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth.
- Author
-
Park SI, Lee C, Sadler WD, Koh AJ, Jones J, Seo JW, Soki FN, Cho SW, Daignault SD, and McCauley LK
- Subjects
- Animals, Antigens, Surface metabolism, CD11b Antigen analysis, Cell Line, Tumor, Cell Proliferation, Dogs, Humans, Male, Mice, Mice, Nude, Prostatic Neoplasms genetics, Tumor Microenvironment physiology, Bone Marrow Cells physiology, Feedback, Physiological physiology, Parathyroid Hormone-Related Protein physiology, Prostatic Neoplasms pathology
- Abstract
In the tumor microenvironment, CD11b(+)Gr1(+) bone marrow-derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone-related protein (PTHrP) potentiates CD11b(+)Gr1(+) cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b(+)Gr1(+) cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b(+)Gr1(+) cell-derived MMP-9 but not tumor-derived VEGF-A. CD11b(+)Gr1(+) cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor-derived PTHrP potentiates this activity of CD11b(+)Gr1(+) cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b(+)Gr1(+) cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b(+)Gr1(+) cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer-derived PTHrP acts in the bone marrow to potentiate CD11b(+)Gr1(+) cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth., (©2013 AACR)
- Published
- 2013
- Full Text
- View/download PDF
44. The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.
- Author
-
Cho SW, Pirih FQ, Koh AJ, Michalski M, Eber MR, Ritchie K, Sinder B, Oh S, Al-Dujaili SA, Lee J, Kozloff K, Danciu T, Wronski TJ, and McCauley LK
- Subjects
- Animals, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Bone and Bones cytology, Bone and Bones drug effects, Bone and Bones metabolism, Cell Differentiation drug effects, Cells, Cultured, Cytokine Receptor gp130 genetics, Cytokine Receptor gp130 metabolism, Female, Flow Cytometry, Hematopoietic Stem Cells metabolism, Interleukin-6 genetics, Interleukin-6 metabolism, Interleukin-6 pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Osteoblasts cytology, Osteoblasts drug effects, Osteoblasts metabolism, Phosphorylation drug effects, Receptors, Interleukin-6 genetics, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Solubility, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Hematopoietic Stem Cells drug effects, Osteogenesis drug effects, Parathyroid Hormone pharmacology, Receptors, Interleukin-6 metabolism
- Abstract
Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-β1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.
- Published
- 2013
- Full Text
- View/download PDF
45. Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis.
- Author
-
Park SI, Liao J, Berry JE, Li X, Koh AJ, Michalski ME, Eber MR, Soki FN, Sadler D, Sud S, Tisdelle S, Daignault SD, Nemeth JA, Snyder LA, Wronski TJ, Pienta KJ, and McCauley LK
- Subjects
- Animals, Antineoplastic Agents, Alkylating adverse effects, Bone Marrow drug effects, Cell Line, Tumor, Chemokine CCL2 pharmacology, Cyclophosphamide adverse effects, Docetaxel, Humans, Interleukin-6 pharmacology, Male, Mice, Myeloid Cells drug effects, Neoplasm Transplantation, Taxoids pharmacology, Antineoplastic Agents, Alkylating pharmacology, Bone Neoplasms secondary, Cyclophosphamide pharmacology, Prostatic Neoplasms pathology
- Abstract
A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone. Priming the murine host with cyclophosphamide before intracardiac tumor cell inoculation was found to significantly promote tumor localization and subsequent growth in bone. Shortly after cyclophosphamide treatment, there was an abrupt expansion of myeloid lineage cells in the bone marrow and the peripheral blood, associated with increases in cytokines with myelogenic potential such as C-C chemokine ligand (CCL)2, interleukin (IL)-6, and VEGF-A. More importantly, neutralizing host-derived murine CCL2, but not IL-6, in the premetastatic murine host significantly reduced the prometastatic effects of cyclophosphamide. Together, our findings suggest that bone marrow perturbation by cytotoxic chemotherapy can contribute to bone metastasis via a transient increase in bone marrow myeloid cells and myelogenic cytokines. These changes can be reversed by inhibition of CCL2., (©2012 AACR.)
- Published
- 2012
- Full Text
- View/download PDF
46. Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis.
- Author
-
Li X, Koh AJ, Wang Z, Soki FN, Park SI, Pienta KJ, and McCauley LK
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, CARD Signaling Adaptor Proteins, Calcium-Calmodulin-Dependent Protein Kinases genetics, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Death-Associated Protein Kinases, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Models, Biological, Prostatic Neoplasms genetics, Bone Neoplasms secondary, Megakaryocytes cytology, Prostatic Neoplasms pathology
- Abstract
Prostate cancer cells commonly spread through the circulation, but few successfully generate metastatic foci in bone. Osteoclastic cellular activity has been proposed as an initiating event for skeletal metastasis. Megakaryocytes (MKs) inhibit osteoclastogenesis, which could have an impact on tumor establishment in bone. Given the location of mature MKs at vascular sinusoids, they may be the first cells to physically encounter cancer cells as they enter the bone marrow. Identification of the interaction between MKs and prostate cancer cells was the focus of this study. K562 (human MK precursors) and primary MKs derived from mouse bone marrow hematopoietic precursor cells potently suppressed prostate carcinoma PC-3 cells in coculture. The inhibitory effects were specific to prostate carcinoma cells and were enhanced by direct cell-cell contact. Flow cytometry for propidium iodide (PI) and annexin V supported a proapoptotic role for K562 cells in limiting PC-3 cells. Gene expression analysis revealed reduced mRNA levels for cyclin D1, whereas mRNA levels of apoptosis-associated specklike protein containing a CARD (ASC) and death-associated protein kinase 1 (DAPK1) were increased in PC-3 cells after coculture with K562 cells. Recombinant thrombopoietin (TPO) was used to expand MKs in the marrow and resulted in decreased skeletal lesion development after intracardiac tumor inoculation. These novel findings suggest a potent inhibitory role of MKs in prostate carcinoma cell growth in vitro and in vivo. This new finding, of an interaction of metastatic tumors and hematopoietic cells during tumor colonization in bone, ultimately will lead to improved therapeutic interventions for prostate cancer patients., (© 2011 American Society for Bone and Mineral Research.)
- Published
- 2011
- Full Text
- View/download PDF
47. Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells.
- Author
-
Chen HL, Demiralp B, Schneider A, Koh AJ, Silve C, Wang CY, and McCauley LK
- Subjects
- 3T3 Cells, Adenylyl Cyclases metabolism, Animals, Blotting, Northern, Blotting, Western, Cell Line, Cell Survival, Cloning, Molecular, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Dexamethasone pharmacology, Enzyme-Linked Immunosorbent Assay, Mesoderm metabolism, Mice, Mice, Inbred C3H, Osteocalcin biosynthesis, Osteocalcin metabolism, Parathyroid Hormone-Related Protein, Phosphorylation, Plasmids metabolism, Protein Binding, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Receptors, Parathyroid Hormone metabolism, Receptors, Parathyroid Hormone physiology, Time Factors, Transfection, Apoptosis, Mesoderm cytology, Parathyroid Hormone physiology, Protein Serine-Threonine Kinases, Proteins physiology
- Abstract
During bone formation, multipotential mesenchymal cells proliferate and differentiate into osteoblasts, and subsequently many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors. Furthermore, the effects of PTH and PTHrP on apoptosis were dramatically dependent on cell status. In preconfluent C3H10T1/2 and MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced reduction in cell viability, which was dependent on cAMP activation. Conversely, PTH and PTHrP resulted in reduced cell viability in postconfluent cells, which was also dependent on cAMP activation. Further, the proapoptotic-like effects were associated with an inhibition of Akt phosphorylation. These data suggest that parathyroid hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at least in part via the protein kinase A pathway.
- Published
- 2002
- Full Text
- View/download PDF
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