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2. Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

Author

Dole, Neha S, Mazur, Courtney M, Acevedo, Claire, Lopez, Justin P, Monteiro, David A, Fowler, Tristan W, Gludovatz, Bernd, Walsh, Flynn, Regan, Jenna N, Messina, Sara, Evans, Daniel S, Lang, Thomas F, Zhang, Bin, Ritchie, Robert O, Mohammad, Khalid S, and Alliston, Tamara

Subjects
Biochemistry and Cell Biology, Biological Sciences, Women's Health, Osteoporosis, Aging, 1.1 Normal biological development and functioning, Animals, Bone Remodeling, Bone and Bones, Cell Line, Immunohistochemistry, Male, Mice, Osteocytes, Signal Transduction, Transforming Growth Factor beta, TGF-β, bone fragility, bone quality, osteocyte, perilacunar/canalicular remodeling, Medical Physiology, Biological sciences
Abstract

Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy-/-), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.

Published
2017

6. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.

Author

Dawalibi, Ahmad, Alosaimi, Amal Ahmed, and Mohammad, Khalid S.

Subjects
CANCER cells, BONE metastasis, PROGNOSIS, BONE cells, IMMUNOREGULATION
Abstract

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Author

Liu, Yang, primary, Reiken, Steven, additional, Dridi, Haikel, additional, Yuan, Qi, additional, Mohammad, Khalid S., additional, Trivedi, Trupti, additional, Miotto, Marco C., additional, Wedderburn-Pugh, Kaylee, additional, Sittenfeld, Leah, additional, Kerley, Ynez, additional, Meyer, Jill A., additional, Peters, Jonathan S., additional, Persohn, Scott C., additional, Bedwell, Amanda A., additional, Figueiredo, Lucas L., additional, Suresh, Sukanya, additional, She, Yun, additional, Soni, Rajesh Kumar, additional, Territo, Paul R., additional, Marks, Andrew R., additional, and Guise, Theresa A., additional

Published
2023
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9. Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone.

Author

Mohammad, Khalid S, Chen, Carol G, Balooch, Guive, Stebbins, Elizabeth, McKenna, C Ryan, Davis, Holly, Niewolna, Maria, Peng, Xiang Hong, Nguyen, Daniel HN, Ionova-Martin, Sophi S, Bracey, John W, Hogue, William R, Wong, Darren H, Ritchie, Robert O, Suva, Larry J, Derynck, Rik, Guise, Theresa A, and Alliston, Tamara

Subjects
Bone and Bones, Bone Matrix, Osteoclasts, Osteoblasts, Animals, Mice, Inbred C57BL, Mice, Bone Resorption, Receptor, EphB4, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Protein Kinase Inhibitors, Cell Differentiation, Calcification, Physiologic, Bone Development, Bone Density, Female, Male, Core Binding Factor Alpha 1 Subunit, Receptor, Transforming Growth Factor-beta Type I, Protein Serine-Threonine Kinases, Osteoporosis, Musculoskeletal, General Science & Technology
Abstract

During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI) kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

Published
2009

12. Zoledronic acid improves bone quality and muscle function in a high bone turnover state

Author

Trivedi, Trupti, primary, Manaa, Mohamed, additional, John, Sutha, additional, Reiken, Steven, additional, Murthy, Sreemala, additional, Pagnotti, Gabriel M., additional, Dole, Neha S., additional, She, Yun, additional, Suresh, Sukanya, additional, Hain, Brian A., additional, Regan, Jenna, additional, Ofer, Rachel, additional, Wright, Laura, additional, Robling, Alex, additional, Cao, Xu, additional, Alliston, Tamara, additional, Marks, Andrew R., additional, Waning, David L., additional, Mohammad, Khalid S., additional, and Guise, Theresa A., additional

Published
2023
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14. Zoledronic acid improves bone quality and muscle function in a high bone turnover state

Author

Trivedi, Trupti, Manaa, Mohamed, John, Sutha, Reiken, Steven, Murthy, Sreemala, Pagnotti, Gabriel M., Dole, Neha S., She, Yun, Suresh, Sukanya, Hain, Brian A., Regan, Jenna, Ofer, Rachel, Wright, Laura, Robling, Alex, Cao, Xu, Alliston, Tamara, Marks, Andrew R., Waning, David L., Mohammad, Khalid S., and Guise, Theresa A.

Subjects
Article
Abstract

SUMMARY: Zoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGFβ release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. CONTEXT AND SIGNIFICANCE: TGFβ is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGFβ causes several bone disorders and skeletal muscle weakness. Reducing excess TGFβ release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acid’s benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

Published
2023

15. TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone

Author

Saito, Hiroaki, Gasser, Andreas, Bolamperti, Simona, Maeda, Miki, Matthies, Levi, Jähn, Katharina, Long, Courtney L., Schlüter, Hartmut, Kwiatkowski, Marcel, Saini, Vaibhav, Pajevic, Paola Divieti, Bellido, Teresita, van Wijnen, Andre J., Mohammad, Khalid S., Guise, Theresa A., Taipaleenmäki, Hanna, and Hesse, Eric

Published
2019
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16. Supplementary Table 2 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Author

Pollari, Sirkku, primary, Käkönen, Rami S., primary, Mohammad, Khalid S., primary, Rissanen, Jukka P., primary, Halleen, Jussi M., primary, Wärri, Anni, primary, Nissinen, Liisa, primary, Pihlavisto, Marjo, primary, Marjamäki, Anne, primary, Perälä, Merja, primary, Guise, Theresa A., primary, Kallioniemi, Olli, primary, and Käkönen, Sanna-Maria, primary

Published
2023
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17. Supplementary Figure 3 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Author

Pollari, Sirkku, primary, Käkönen, Rami S., primary, Mohammad, Khalid S., primary, Rissanen, Jukka P., primary, Halleen, Jussi M., primary, Wärri, Anni, primary, Nissinen, Liisa, primary, Pihlavisto, Marjo, primary, Marjamäki, Anne, primary, Perälä, Merja, primary, Guise, Theresa A., primary, Kallioniemi, Olli, primary, and Käkönen, Sanna-Maria, primary

Published
2023
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18. Supplementary Figure 1 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Author

Pollari, Sirkku, primary, Käkönen, Rami S., primary, Mohammad, Khalid S., primary, Rissanen, Jukka P., primary, Halleen, Jussi M., primary, Wärri, Anni, primary, Nissinen, Liisa, primary, Pihlavisto, Marjo, primary, Marjamäki, Anne, primary, Perälä, Merja, primary, Guise, Theresa A., primary, Kallioniemi, Olli, primary, and Käkönen, Sanna-Maria, primary

Published
2023
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19. Supplementary Table 1 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Author

Pollari, Sirkku, primary, Käkönen, Rami S., primary, Mohammad, Khalid S., primary, Rissanen, Jukka P., primary, Halleen, Jussi M., primary, Wärri, Anni, primary, Nissinen, Liisa, primary, Pihlavisto, Marjo, primary, Marjamäki, Anne, primary, Perälä, Merja, primary, Guise, Theresa A., primary, Kallioniemi, Olli, primary, and Käkönen, Sanna-Maria, primary

Published
2023
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20. Supplementary Figure 2 from Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Author

Pollari, Sirkku, primary, Käkönen, Rami S., primary, Mohammad, Khalid S., primary, Rissanen, Jukka P., primary, Halleen, Jussi M., primary, Wärri, Anni, primary, Nissinen, Liisa, primary, Pihlavisto, Marjo, primary, Marjamäki, Anne, primary, Perälä, Merja, primary, Guise, Theresa A., primary, Kallioniemi, Olli, primary, and Käkönen, Sanna-Maria, primary

Published
2023
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21. Data from Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Author

Ross, Michael H., primary, Esser, Alison K., primary, Fox, Gregory C., primary, Schmieder, Anne H., primary, Yang, Xiaoxia, primary, Hu, Grace, primary, Pan, Dipanjan, primary, Su, Xinming, primary, Xu, Yalin, primary, Novack, Deborah V., primary, Walsh, Thomas, primary, Colditz, Graham A., primary, Lukaszewicz, Gabriel H., primary, Cordell, Elizabeth, primary, Novack, Joshua, primary, Fitzpatrick, James A. J., primary, Waning, David L., primary, Mohammad, Khalid S., primary, Guise, Theresa A., primary, Lanza, Gregory M., primary, and Weilbaecher, Katherine N., primary

Published
2023
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22. Supplemental figure legend from Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

Author

Xu, Linlin, primary, Mohammad, Khalid S., primary, Wu, Hao, primary, Crean, Colin, primary, Poteat, Bradley, primary, Cheng, Yinghua, primary, Cardoso, Angelo A., primary, Machal, Christophe, primary, Hanenberg, Helmut, primary, Abonour, Rafat, primary, Kacena, Melissa A., primary, Chirgwin, John, primary, Suvannasankha, Attaya, primary, and Srour, Edward F., primary

Published
2023
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23. Data from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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24. Supplementary figure 2 from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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25. Supplemental Information from Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Author

Ross, Michael H., primary, Esser, Alison K., primary, Fox, Gregory C., primary, Schmieder, Anne H., primary, Yang, Xiaoxia, primary, Hu, Grace, primary, Pan, Dipanjan, primary, Su, Xinming, primary, Xu, Yalin, primary, Novack, Deborah V., primary, Walsh, Thomas, primary, Colditz, Graham A., primary, Lukaszewicz, Gabriel H., primary, Cordell, Elizabeth, primary, Novack, Joshua, primary, Fitzpatrick, James A. J., primary, Waning, David L., primary, Mohammad, Khalid S., primary, Guise, Theresa A., primary, Lanza, Gregory M., primary, and Weilbaecher, Katherine N., primary

Published
2023
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26. Data from Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

Author

Xu, Linlin, primary, Mohammad, Khalid S., primary, Wu, Hao, primary, Crean, Colin, primary, Poteat, Bradley, primary, Cheng, Yinghua, primary, Cardoso, Angelo A., primary, Machal, Christophe, primary, Hanenberg, Helmut, primary, Abonour, Rafat, primary, Kacena, Melissa A., primary, Chirgwin, John, primary, Suvannasankha, Attaya, primary, and Srour, Edward F., primary

Published
2023
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27. Supplemental Table 1 from Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

Author

Xu, Linlin, primary, Mohammad, Khalid S., primary, Wu, Hao, primary, Crean, Colin, primary, Poteat, Bradley, primary, Cheng, Yinghua, primary, Cardoso, Angelo A., primary, Machal, Christophe, primary, Hanenberg, Helmut, primary, Abonour, Rafat, primary, Kacena, Melissa A., primary, Chirgwin, John, primary, Suvannasankha, Attaya, primary, and Srour, Edward F., primary

Published
2023
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28. Supplementary figure 3 from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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29. Supplementary figure legends from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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30. Supplementary figure 1 from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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31. Supplemental Figure S3 from Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Author

Ross, Michael H., primary, Esser, Alison K., primary, Fox, Gregory C., primary, Schmieder, Anne H., primary, Yang, Xiaoxia, primary, Hu, Grace, primary, Pan, Dipanjan, primary, Su, Xinming, primary, Xu, Yalin, primary, Novack, Deborah V., primary, Walsh, Thomas, primary, Colditz, Graham A., primary, Lukaszewicz, Gabriel H., primary, Cordell, Elizabeth, primary, Novack, Joshua, primary, Fitzpatrick, James A. J., primary, Waning, David L., primary, Mohammad, Khalid S., primary, Guise, Theresa A., primary, Lanza, Gregory M., primary, and Weilbaecher, Katherine N., primary

Published
2023
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32. Supplemental figures 1-7 from Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

Author

Xu, Linlin, primary, Mohammad, Khalid S., primary, Wu, Hao, primary, Crean, Colin, primary, Poteat, Bradley, primary, Cheng, Yinghua, primary, Cardoso, Angelo A., primary, Machal, Christophe, primary, Hanenberg, Helmut, primary, Abonour, Rafat, primary, Kacena, Melissa A., primary, Chirgwin, John, primary, Suvannasankha, Attaya, primary, and Srour, Edward F., primary

Published
2023
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33. Supplementary methods from Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Author

Delgado-Calle, Jesus, primary, Anderson, Judith, primary, Cregor, Meloney D., primary, Hiasa, Masahiro, primary, Chirgwin, John M., primary, Carlesso, Nadia, primary, Yoneda, Toshiyuki, primary, Mohammad, Khalid S., primary, Plotkin, Lilian I., primary, Roodman, G. David, primary, and Bellido, Teresita, primary

Published
2023
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37. Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice

Author

Pagnotti, Gabriel M., primary, Trivedi, Trupti, additional, Wright, Laura E., additional, John, Sutha K., additional, Murthy, Sreemala, additional, Pattyn, Ryan R., additional, Willis, Monte S., additional, She, Yun, additional, Suresh, Sukanya, additional, Thompson, William R., additional, Rubin, Clinton T., additional, Mohammad, Khalid S., additional, and Guise, Theresa A., additional

Published
2023
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39. Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells

Author

Singh, Pratibha, Hoggat, Jonathan, Kamocka, Malgorzata M., Mohammad, Khalid S., Saunders, Mary R., Li, Hongge, Speth, Jennifer, Carlesso, Nadia, Guise, Theresa A., and Pelus, Louis M.

Subjects
Neuropeptide Y -- Analysis, Cytokines -- Analysis, Hematopoietic stem cells -- Research -- Care and treatment, Health care industry
Abstract

Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions., Introduction Hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches associated with supporting cells that regulate quiescence and proliferative fate decisions (1-3). At homeostasis, only a small [...]

Published
2017
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45. Excess TGF-[beta] mediates muscle weakness associated with bone metastases in mice

Author

Waning, David L, Mohammad, Khalid S, Reiken, Steven, Xie, Wenjun, Andersson, Daniel C, John, Sutha, Chiechi, Antonella, Wright, Laura E, Umanskaya, Alisa, Niewolna, Maria, Trivedi, Trupti, Charkhzarrin, Sahba, Khatiwada, Pooja, Wronska, Anetta, Haynes, Ashley, Benassi, Maria Serena, Witzmann, Frank A, Zhen, Gehua, Wang, Xiao, Cao, Xu, Roodman, G David, Marks, Andrew R, and Guise, Theresa A

Subjects
Skeletal muscle -- Analysis -- Care and treatment, Transforming growth factors -- Research, Prostate cancer -- Care and treatment, Bone diseases -- Care and treatment, Genetically modified mice -- Research, Biological sciences, Health
Abstract

Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases--representing breast, lung and prostate cancers, as well as multiple myeloma--exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-[beta], released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca[sup.2+]) release channel (RyR1). The oxidized RyR1 channels leaked Ca[sup.2+], resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-[beta] signaling, TGF-[beta] release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-[beta] activity. Thus, pathological TGF-[beta] release from bone contributes to muscle weakness by decreasing Ca[sup.2+]-induced muscle force production., Author(s): David L Waning [1]; Khalid S Mohammad [1]; Steven Reiken [2]; Wenjun Xie [2]; Daniel C Andersson [2]; Sutha John [1]; Antonella Chiechi [1]; Laura E Wright [1]; Alisa [...]

Published
2015
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50. Differential stem- and progenitor-cell trafficking by prostaglandin [E.sub.2]

Author

Hoggatt, Jonathan, Mohammad, Khalid S., Singh, Pratibha, Hoggatt, Amber F., Chitteti, Brahmananda R., Speth, Jennifer M., Hu, Peirong, Poteat, Bradley A., Stilger, Kayla N., Ferraro, Francesca, Silberstein, Lev, Wong, Frankie K., Farag, Sherif S., Czader, Magdalena, Milne, Ginger L., Breyer, Richard M., Serezani, Carlos H., Scadden, David T., Guise, Theresa A., Srour, Edward F., and Pelus, Louis M.

Subjects
Prostaglandins -- Research, Hematopoietic stem cells -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside [...]

Published
2013
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