Browsing by Author "Balanta-Melo, Julián"

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    Fragile X Messenger Ribonucleoprotein 1 (FMR1), a novel inhibitor of osteoblast/osteocyte differentiation, regulates bone formation, mass, and strength in young and aged male and female mice
    (Springer Nature, 2023-05-17) Deosthale, Padmini; Balanta-Melo, Julián; Creecy, Amy; Liu, Chongshan; Marcial, Alejandro; Morales, Laura; Cridlin, Julita; Robertson, Sylvia; Okpara, Chiebuka; Sanchez, David J.; Ayoubi, Mahdi; Lugo, Joaquín N.; Hernandez, Christopher J.; Wallace, Joseph M.; Plotkin, Lilian I.; Anatomy, Cell Biology and Physiology, School of Medicine
    Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene mutations lead to fragile X syndrome, cognitive disorders, and, in some individuals, scoliosis and craniofacial abnormalities. Four-month-old (mo) male mice with deletion of the FMR1 gene exhibit a mild increase in cortical and cancellous femoral bone mass. However, consequences of absence of FMR1 in bone of young/aged male/female mice and the cellular basis of the skeletal phenotype remain unknown. We found that absence of FMR1 results in improved bone properties with higher bone mineral density in both sexes and in 2- and 9-mo mice. The cancellous bone mass is higher only in females, whereas, cortical bone mass is higher in 2- and 9-mo males, but higher in 2- and lower in 9-mo female FMR1-knockout mice. Furthermore, male bones show higher biomechanical properties at 2mo, and females at both ages. Absence of FMR1 increases osteoblast/mineralization/bone formation and osteocyte dendricity/gene expression in vivo/ex vivo/in vitro, without affecting osteoclasts in vivo/ex vivo. Thus, FMR1 is a novel osteoblast/osteocyte differentiation inhibitor, and its absence leads to age-, site- and sex-dependent higher bone mass/strength.
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    In vitro and in vivo studies using non-traditional bisphosphonates
    (Elsevier, 2020-05) Plotkin, Lilian I.; Buvinic, Sonja; Balanta-Melo, Julián; Anatomy and Cell Biology, School of Medicine
    Non-traditional bisphosphonates, that is, bisphosphonates that do not inhibit osteoclast viability or function, were initially reported in the 1990s by Socrates Papapoulos' group. Originally designed to study the role of the R1 residue of aminobisphosphonates on bisphosphonate affinity for hydroxyapatite, these modified bisphosphonates retained similar affinity for mineralized bone as their parent compounds, but they lacked the potential to inhibit the mevalonate pathway or bone resorption. We found that, similar to classical bisphosphonates, these non-traditional compounds prevented osteoblast and osteocyte apoptosis in vitro through a pathway that requires the expression of the gap junction protein connexin 43, and the activation of the Src/MEK/ERK signaling pathway. Furthermore, one of those compounds named IG9402 (also known as amino-olpadronate or lidadronate), was able to inhibit osteoblast and osteocyte apoptosis, without affecting osteoclast number or bone resorption in vivo in a model of glucocorticoid-induced osteoporosis. IG9402 administration also ameliorated the decrease in bone mass and in bone mechanical properties induced by glucocorticoids. Similarly, IG9402 prevented apoptosis of osteoblastic cells in a model of immobilization due to hindlimb unloading. However, in this case, the bisphosphonate was not able to preserve the bone mass, and only partially prevented the decrease in bone mechanical properties induced by immobilization. The effect of IG9402 administration was also tested in a mouse model of masticatory hypofunction through the induction of masseter muscle atrophy by unilateral injection of botulinum toxin type A (BoNTA). IG9402 partially inhibited the loss of trabecular bone microstructure in the mandibular condyle, but not the decrease in masseter muscle mass induced by BoNTA administration. In summary, these non-traditional bisphosphonates that lack anti-resorptive activity but are able to preserve osteoblast and osteocyte viability could constitute useful tools to study the consequences of preventing apoptosis of osteoblastic cells in animal models. Furthermore, they could be used to treat conditions associated with reduced bone mass and increased bone fragility in which a reduction of bone remodeling is not desirable.
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    Musculoskeletal Deficits and Cognitive Impairment: Epidemiological Evidence and Biological Mechanisms
    (Springer, 2022) Sui, Sophia X.; Balanta-Melo, Julián; Pasco, Julie A.; Plotkin, Lilian I.; Anatomy, Cell Biology and Physiology, School of Medicine
    Purpose of review: Cognitive impairment is associated with obesity, sarcopenia, and osteoporosis. However, no critical appraisal of the literature on the relationship between musculoskeletal deficits and cognitive impairment, focusing on the epidemiological evidence and biological mechanisms, has been published to date. Herein, we critically evaluate the literature published over the past 3 years, emphasizing interesting and important new findings, and provide an outline of future directions that will improve our understanding of the connections between the brain and the musculoskeletal system. Recent findings: Recent literature suggests that musculoskeletal deficits and cognitive impairment share pathophysiological pathways and risk factors. Cytokines and hormones affect both the brain and the musculoskeletal system; yet, lack of unified definitions and standards makes it difficult to compare studies. Interventions designed to improve musculoskeletal health are plausible means of preventing or slowing cognitive impairment. We highlight several musculoskeletal health interventions that show potential in this regard.
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    Unilateral Hypofunction of the Masseter Leads to Molecular and 3D Morphometric Signs of Atrophy in Ipsilateral Agonist Masticatory Muscles in Adult Mice
    (MDPI, 2023-09-29) Balanta-Melo, Julián; Eyquem-Reyes, Andrea; Blanco, Noelia; Vásquez, Walter; Kupczik, Kornelius; Toro-Ibacache, Viviana; Buvinic, Sonja; Anatomy, Cell Biology and Physiology, School of Medicine
    Mice are commonly used to study mandibular dynamics due to their similarity in chewing cycle patterns with humans. Adult mice treated unilaterally with botulinum toxin type A (BoNTA) in the masseter exhibit atrophy of this muscle characterized by an increase in the gene expression of atrophy-related molecular markers, and a reduction in both muscle fiber diameter and muscle mass at 14d. However, the impact of this muscle imbalance on the non-treated masticatory muscles remains unexplored. Here, we hypothesize that the unilateral masseter hypofunction leads to molecular and 3D morphometric signs of atrophy of the masseter and its agonist masticatory muscles in adult mice. Twenty-three 8-week-old male BALB/c mice received a single injection of BoNTA in the right masseter, whereas the left masseter received the same volume of saline solution (control side). Animals were euthanized at 2d, 7d, and 14d, and the masticatory muscles were analyzed for mRNA expression. Five heads were harvested at 14d, fixed, stained with a contrast-enhanced agent, and scanned using X-ray microtomography. The three-dimensional morphometric parameters (the volume and thickness) from muscles in situ were obtained. Atrogin-1/MAFbx, MuRF-1, and Myogenin mRNA gene expression were significantly increased at 2 and 7d for both the masseter and temporalis from the BoNTA side. For medial pterygoid, increased mRNA gene expression was found at 7d for Atrogin-1/MAFbx and at 2d–7d for Myogenin. Both the volume and thickness of the masseter, temporalis, and medial pterygoid muscles from the BoNTA side were significantly reduced at 14d. In contrast, the lateral pterygoid from the BoNTA side showed a significant increase in volume at 14d. Therefore, the unilateral hypofunction of the masseter leads to molecular and morphological signs of atrophy in both the BoNTA-injected muscle and its agonistic non-injected masticatory muscles. The generalized effect on the mouse masticatory apparatus when one of its components is intervened suggests the need for more clinical studies to determine the safety of BoNTA usage in clinical dentistry.