Browsing by Author "Brun, Lucas R."

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    Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
    (Wiley, 2017-03-01) Davis, Hannah M.; Pacheco-Costa, Rafael; Atkinson, Emily G.; Brun, Lucas R.; Gortazar, Arancha R.; Harris, Julia; Hiasa, Masahiro; Bolarinwa, Surajudeen A.; Yoneda, Toshiyuki; Ivan, Mircea; Bruzzaniti, Angela; Bellido, Teresita; Plotkin, Lilian I.; Department of Anatomy & Cell Biology, IU School of Medicine
    Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
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    Editorial: Bone inside-out and outside-in signals: Control of body homeostasis
    (Frontiers Media, 2023-01-06) Sankar, Uma; Brun, Lucas R.; Plotkin, Lilian I.; Anatomy, Cell Biology and Physiology, School of Medicine
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    Increased Osteoblastic and Osteocytic in Vitro Cell Viability by Yerba Mate (Ilex paraguariensis)
    (Korean Society for Bone and Mineral Research, 2024) Villarreal, Laureana; Sanz, Natasha; Buiatti Fagalde, Florencia; D’Andrea, Florencia; Lombarte, Mercedes; Rico, María J.; Rozados, Viviana R.; Scharovsky, O. Graciela; Plotkin, Lilian I.; Di Loreto, Verónica E.; Brun, Lucas R.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Yerba mate (YM, Ilex paraguariensis) consumption beneficially affects the bones. However, whether YM components exert their effect on bone cells directly remains elusive. Methods: We evaluated how main YM components affect osteoblastic (MC3T3-E1) and osteocytic (MLO-Y4) cells in vitro when administered separately or in an aqueous extract. MC3T3-E1 and MLO-Y4 cells were exposed to three different experimental conditions: (1) Caffeine, chlorogenic acid, and their combinations; (2) Caffeine, rutin, and their combinations; (3) Aqueous YM extract. Results: All polyphenol and caffeine concentrations as well as that of their tested combinations significantly increased MC3T3-E1 cell viability from 16.6% to 34.8% compared to the control. In MLO-Y4 cells, the lowest rutin and the two highest caffeine concentrations significantly increased cell viability by 11.9, 14.9, and 13.7%, respectively. While rutin and caffeine combinations tended to increase MLO-Y4 cell viability, different chlorogenic acid and caffeine combinations did not affect it. Finally, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viability compared to the control without treatment. Conclusions: YM components (rutin, chlorogenic acid, and caffeine) positively affected bone cells, mainly pre-osteoblast cells. Moreover, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viabilities indicating an additional relevant nutritional property of YM infusion. Further studies would be required to elucidate the underlying effector mechanism of YM on the bones and its relationship with previously described in vivo positive effects.
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    Messages from the Mineral: How Bone Cells Communicate with Other Tissues
    (Springer, 2023) Plotkin, Lilian I.; Sanz, Natasha; Brun, Lucas R.; Anatomy, Cell Biology and Physiology, School of Medicine
    Bone is a highly dynamic tissue, and the constant actions of bone-forming and bone-resorbing cells are responsible for attaining peak bone mass, maintaining bone mass in the adults, and the subsequent bone loss with aging and menopause, as well as skeletal complications of diseases and drug side-effects. It is now accepted that the generation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts is modulated by osteocytes, osteoblast-derived cells embedded in the bone matrix. The interaction among bone cells occurs through direct contact and via secreted molecules. In addition to the regulation of bone cell function, molecules released by these cells are also able to reach the circulation and have effects in other tissues and organs in healthy individuals. Moreover, bone cell products have also been associated with the establishment or progression of diseases, including cancer and muscle weakness. In this review, we will discuss the role of bone as an endocrine organ, and the effect of selected, osteoblast-, osteocyte-, and osteoclast-secreted molecules on other tissues.