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The masticatory system is a complex and highly organized group of structures, including craniofacial bones (maxillae and mandible), muscles, teeth, joints, and neurovascular elements. While the musculoskeletal structures of the head and neck are known to have a different embryonic origin, morphology, biomechanical demands, and biochemical characteristics than the trunk and limbs, their particular molecular basis and cell biology have been much less explored. In the last decade, the concept of muscle-bone crosstalk has emerged, comprising both the loads generated during muscle contraction and a biochemical component through soluble molecules. Bone cells embedded in the mineralized tissue respond to the biomechanical input by releasing molecular factors that impact the homeostasis of the attaching skeletal muscle. In the same way, muscle-derived factors act as soluble signals that modulate the remodeling process of the underlying bones. This concept of muscle-bone crosstalk at a molecular level is particularly interesting in the mandible, due to its tight anatomical relationship with one of the biggest and strongest masticatory muscles, the masseter. However, despite the close physical and physiological interaction of both tissues for proper functioning, this topic has been poorly addressed. Here we present one of the most detailed reviews of the literature to date regarding the biomechanical and biochemical interaction between muscles and bones of the masticatory system, both during development and in physiological or pathological remodeling processes. Evidence related to how masticatory function shapes the craniofacial bones is discussed, and a proposal presented that the masticatory muscles and craniofacial bones serve as secretory tissues. We furthermore discuss our current findings of myokines-release from masseter muscle in physiological conditions, during functional adaptation or pathology, and their putative role as bone-modulators in the craniofacial system. Finally, we address the physiological implications of the crosstalk between muscles and bones in the masticatory system, analyzing pathologies or clinical procedures in which the alteration of one of them affects the homeostasis of the other. Unveiling the mechanisms of muscle-bone crosstalk in the masticatory system opens broad possibilities for understanding and treating temporomandibular disorders, which severely impair the quality of life, with a high cost for diagnosis and management.
Sonja Buvinic; Julián Balanta-Melo; Kornelius Kupczik; Walter Vásquez; Carolina Beato; Viviana Toro-Ibacache. Muscle-Bone Crosstalk in the Masticatory System: From Biomechanical to Molecular Interactions. Frontiers in Endocrinology 2021, 11, 1 .
AMA StyleSonja Buvinic, Julián Balanta-Melo, Kornelius Kupczik, Walter Vásquez, Carolina Beato, Viviana Toro-Ibacache. Muscle-Bone Crosstalk in the Masticatory System: From Biomechanical to Molecular Interactions. Frontiers in Endocrinology. 2021; 11 ():1.
Chicago/Turabian StyleSonja Buvinic; Julián Balanta-Melo; Kornelius Kupczik; Walter Vásquez; Carolina Beato; Viviana Toro-Ibacache. 2021. "Muscle-Bone Crosstalk in the Masticatory System: From Biomechanical to Molecular Interactions." Frontiers in Endocrinology 11, no. : 1.
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.
Lilian I. Plotkin; Sonja Buvinic; Julián Balanta-Melo. In vitro and in vivo studies using non-traditional bisphosphonates. Bone 2020, 134, 115301 .
AMA StyleLilian I. Plotkin, Sonja Buvinic, Julián Balanta-Melo. In vitro and in vivo studies using non-traditional bisphosphonates. Bone. 2020; 134 ():115301.
Chicago/Turabian StyleLilian I. Plotkin; Sonja Buvinic; Julián Balanta-Melo. 2020. "In vitro and in vivo studies using non-traditional bisphosphonates." Bone 134, no. : 115301.
The injection of botulinum toxin type A (BoNT/A) in the masticatory muscles, to cause its temporary paralysis, is a widely used intervention for clinical disorders such as oromandibular dystonia, sleep bruxism, and aesthetics (i.e., masseteric hypertrophy). Considering that muscle contraction is required for mechano-transduction to maintain bone homeostasis, it is relevant to address the bone adverse effects associated with muscle condition after this intervention. Our aim is to condense the current and relevant literature about mandibular bone loss in fully mature mammals after BoNT/A intervention in the masticatory muscles. Here, we compile evidence from animal models (mice, rats, and rabbits) to clinical studies, demonstrating that BoNT/A-induced masticatory muscle atrophy promotes mandibular bone loss. Mandibular bone-related adverse effects involve cellular and metabolic changes, microstructure degradation, and morphological alterations. While bone loss has been detected at the mandibular condyle or alveolar bone, cellular and molecular mechanisms involved in this process must still be elucidated. Further basic research could provide evidence for designing strategies to control the undesired effects on bone during the therapeutic use of BoNT/A. However, in the meantime, we consider it essential that patients treated with BoNT/A in the masticatory muscles be warned about a putative collateral mandibular bone damage.
Julián Balanta-Melo; Viviana Toro-Ibacache; Kornelius Kupczik; Sonja Buvinic. Mandibular Bone Loss after Masticatory Muscles Intervention with Botulinum Toxin: An Approach from Basic Research to Clinical Findings. Toxins 2019, 11, 84 .
AMA StyleJulián Balanta-Melo, Viviana Toro-Ibacache, Kornelius Kupczik, Sonja Buvinic. Mandibular Bone Loss after Masticatory Muscles Intervention with Botulinum Toxin: An Approach from Basic Research to Clinical Findings. Toxins. 2019; 11 (2):84.
Chicago/Turabian StyleJulián Balanta-Melo; Viviana Toro-Ibacache; Kornelius Kupczik; Sonja Buvinic. 2019. "Mandibular Bone Loss after Masticatory Muscles Intervention with Botulinum Toxin: An Approach from Basic Research to Clinical Findings." Toxins 11, no. 2: 84.
Masseter muscle function influences mandibular bone homeostasis. As previously reported, bone resorption markers increased in the mouse mandibular condyle two days after masseter paralysis induced with botulinum toxin type A (BoNTA), followed by local bone loss. This study aimed to evaluate the bone quality of both the mandibular condyle and alveolar process in the mandible of adult mice during the early stage of a BoNTA-induced masseter muscle atrophy, using a combined 3D histomorphometrics and shape analysis approach. Adult BALB/c mice were divided into an untreated control group and an experimental group; the latter received one single BoNTA injection in the right masseter (BoNTA-right) and saline in the left masseter (Saline-left). 3D bone microstructural changes in the mandibular condyle and alveolar process were determined with high-resolution microtomography. Additionally, landmark-based geometric morphometrics was implemented to assess external shape changes. After 2 weeks, masseter mass was significantly reduced (P-value 0.05). Condyle bone quality deteriorates at an early stage of BoNTA-induced masseter muscle atrophy, and before the alveolar process is affected. Since the observed bone microstructural changes resemble those in human temporomandibular joint degenerative disorders, the clinical safety of BoNTA intervention in the masticatory apparatus remains to be clarified.
Julián Balanta-Melo; María Angélica Torres-Quintana; Maximilian Bemmann; Carolina Vega; Constanza González; Kornelius Kupczik; Viviana Toro-Ibacache; Sonja Buvinic. Masseter muscle atrophy impairs bone quality of the mandibular condyle but not the alveolar process early after induction. Journal of Oral Rehabilitation 2018, 46, 233 -241.
AMA StyleJulián Balanta-Melo, María Angélica Torres-Quintana, Maximilian Bemmann, Carolina Vega, Constanza González, Kornelius Kupczik, Viviana Toro-Ibacache, Sonja Buvinic. Masseter muscle atrophy impairs bone quality of the mandibular condyle but not the alveolar process early after induction. Journal of Oral Rehabilitation. 2018; 46 (3):233-241.
Chicago/Turabian StyleJulián Balanta-Melo; María Angélica Torres-Quintana; Maximilian Bemmann; Carolina Vega; Constanza González; Kornelius Kupczik; Viviana Toro-Ibacache; Sonja Buvinic. 2018. "Masseter muscle atrophy impairs bone quality of the mandibular condyle but not the alveolar process early after induction." Journal of Oral Rehabilitation 46, no. 3: 233-241.
Masseter muscle paralysis induced by botulinum toxin type A (BoNTA) evokes subchondral bone loss in mandibular heads of adult rats and growing mice after 4 weeks. However, the primary cellular and molecular events leading to altered bone remodeling remain unexplored. Thus, the aim of the current work has been to assess the molecular response that precedes the early microanatomical changes in the masseter muscle and subchondral bone of the mandibular head in adult mice after BoNTA intervention. A pre-clinical in vivo study was performed by a single intramuscular injection of 0.2 U BoNTA in the right masseter (experimental) of adult BALB/c mice. The contralateral masseter was injected with vehicle (control). Changes in mRNA levels of molecular markers of bone loss or muscle atrophy/regeneration were addressed by qPCR at day 2 or 7, respectively. mRNA levels of receptor activator of nuclear factor-κB ligand (RANKL) was assessed in mandibular heads, whilst mRNA levels of Atrogin-1/MAFbx, MuRF-1 and Myogenin were addressed in masseter muscles. In order to identify the early microanatomical changes at day 14, fiber diameters in transversal sections of masseter muscles were quantified, and histomorphometric analysis was used to determine the bone per tissue area and the trabecular thickness of subchondral bone of the mandibular heads. An increase of up to 4-fold in RANKL mRNA levels were detected in mandibular heads of the BoNTA-injected sides as early as 2 d after intervention. Moreover, a 4-6 fold increase in Atrogin-1/MAFbx and MuRF-1 and an up to 25 fold increase in myogenin mRNA level were detected in masseter muscles 7 d after BoNTA injections. Masseter muscle mass, as well as individual muscle fiber diameter, were significantly reduced in BoNTA-injected side after 14 d post-intervention. At the same time, in the mandibular heads from the treated side, the subchondral bone loss was evinced by a significant reduction in bone per tissue area (- 40%) and trabecular thickness (- 55%). Our results show that masseter muscle paralysis induced by BoNTA leads to significant microanatomical changes by day 14, preceded by molecular changes as early as 2 d in bone, and 7 d in muscle. Therefore, masseter muscle atrophy and subchondral bone loss detected at 14 d are preceded by molecular responses that occur during the first week after BoNTA intervention.
Julián Balanta-Melo; Viviana Toro-Ibacache; Maria Angélica Torres-Quintana; Kornelius Kupczik; Carolina Vega; Camilo Morales; Nadia Hernández-Moya; Manuel Arias-Calderón; Carolina Beato; Sonja Buvinic. Early molecular response and microanatomical changes in the masseter muscle and mandibular head after botulinum toxin intervention in adult mice. Annals of Anatomy - Anatomischer Anzeiger 2018, 216, 112 -119.
AMA StyleJulián Balanta-Melo, Viviana Toro-Ibacache, Maria Angélica Torres-Quintana, Kornelius Kupczik, Carolina Vega, Camilo Morales, Nadia Hernández-Moya, Manuel Arias-Calderón, Carolina Beato, Sonja Buvinic. Early molecular response and microanatomical changes in the masseter muscle and mandibular head after botulinum toxin intervention in adult mice. Annals of Anatomy - Anatomischer Anzeiger. 2018; 216 ():112-119.
Chicago/Turabian StyleJulián Balanta-Melo; Viviana Toro-Ibacache; Maria Angélica Torres-Quintana; Kornelius Kupczik; Carolina Vega; Camilo Morales; Nadia Hernández-Moya; Manuel Arias-Calderón; Carolina Beato; Sonja Buvinic. 2018. "Early molecular response and microanatomical changes in the masseter muscle and mandibular head after botulinum toxin intervention in adult mice." Annals of Anatomy - Anatomischer Anzeiger 216, no. : 112-119.
Julián Balanta-Melo; Sonja Buvinic. Mandibular bone loss: a hidden side effect of botulinum toxin type A injection in masticatory muscles. Journal of Oral Research 2018, 7, 44 -46.
AMA StyleJulián Balanta-Melo, Sonja Buvinic. Mandibular bone loss: a hidden side effect of botulinum toxin type A injection in masticatory muscles. Journal of Oral Research. 2018; 7 (2):44-46.
Chicago/Turabian StyleJulián Balanta-Melo; Sonja Buvinic. 2018. "Mandibular bone loss: a hidden side effect of botulinum toxin type A injection in masticatory muscles." Journal of Oral Research 7, no. 2: 44-46.
Electrical activity regulates the expression of skeletal muscle genes by a process known as "excitation-transcription" (E-T) coupling. We have demonstrated that release of adenosine 5'-triphosphate (ATP) during depolarization activates membrane P2X/P2Y receptors, being the fundamental mediators between electrical stimulation, slow intracellular calcium transients, and gene expression. We propose that this signaling pathway would require the proper coordination between the voltage sensor (dihydropyridine receptor, DHPR), pannexin 1 channels (Panx1, ATP release conduit), nucleotide receptors, and other signaling molecules. The goal of this study was to assess protein-protein interactions within the E-T machinery and to look for novel constituents in order to characterize the signaling complex. Newborn derived myotubes, adult fibers, or triad fractions from rat or mouse skeletal muscles were used. Co-immunoprecipitation, 2D blue native SDS/PAGE, confocal microscopy z-axis reconstruction, and proximity ligation assays were combined to assess the physical proximity of the putative complex interactors. An L6 cell line overexpressing Panx1 (L6-Panx1) was developed to study the influence of some of the complex interactors in modulation of gene expression. Panx1, DHPR, P2Y2 receptor (P2Y2R), and dystrophin co-immunoprecipitated in the different preparations assessed. 2D blue native SDS/PAGE showed that DHPR, Panx1, P2Y2R and caveolin-3 (Cav3) belong to the same multiprotein complex. We observed co-localization and protein-protein proximity between DHPR, Panx1, P2Y2R, and Cav3 in adult fibers and in the L6-Panx1 cell line. We found a very restricted location of Panx1 and Cav3 in a putative T-tubule zone near the sarcolemma, while DHPR was highly expressed all along the transverse (T)-tubule. By Panx1 overexpression, extracellular ATP levels were increased both at rest and after electrical stimulation. Basal mRNA levels of the early gene cfos and the oxidative metabolism markers citrate synthase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were significantly increased by Panx1 overexpression. Interleukin 6 expression evoked by 20-Hz electrical stimulation (270 pulses, 0.3 ms each) was also significantly upregulated in L6-Panx1 cells. We propose the existence of a relevant multiprotein complex that coordinates events involved in E-T coupling. Unveiling the molecular actors involved in the regulation of gene expression will contribute to the understanding and treatment of skeletal muscle disorders due to wrong-expressed proteins, as well as to improve skeletal muscle performance.
Manuel Arias-Calderón; Gonzalo Almarza; Alexis Díaz-Vegas; Ariel Contreras-Ferrat; Denisse Valladares; Mariana Casas; Héctor Toledo; Enrique Jaimovich; Sonja Buvinic. Characterization of a multiprotein complex involved in excitation-transcription coupling of skeletal muscle. Skeletal Muscle 2016, 6, 15 .
AMA StyleManuel Arias-Calderón, Gonzalo Almarza, Alexis Díaz-Vegas, Ariel Contreras-Ferrat, Denisse Valladares, Mariana Casas, Héctor Toledo, Enrique Jaimovich, Sonja Buvinic. Characterization of a multiprotein complex involved in excitation-transcription coupling of skeletal muscle. Skeletal Muscle. 2016; 6 (1):15.
Chicago/Turabian StyleManuel Arias-Calderón; Gonzalo Almarza; Alexis Díaz-Vegas; Ariel Contreras-Ferrat; Denisse Valladares; Mariana Casas; Héctor Toledo; Enrique Jaimovich; Sonja Buvinic. 2016. "Characterization of a multiprotein complex involved in excitation-transcription coupling of skeletal muscle." Skeletal Muscle 6, no. 1: 15.
Interleukin-6 (IL-6) is an important myokine that is highly expressed in skeletal muscle cells upon exercise. We assessed IL-6 expression in response to electrical stimulation (ES) or extracellular ATP as a known mediator of the excitation-transcription mechanism in skeletal muscle. We examined whether the canonical signaling cascade downstream of IL-6 (IL-6/JAK2/STAT3) also responds to muscle cell excitation, concluding that IL-6 influences its own expression through a positive loop. Either ES or exogenous ATP (100 μM) increased both IL-6 expression and p-STAT3 levels in rat myotubes, a process inhibited by 100 μM suramin and 2 U/ml apyrase. ATP also evoked IL-6 expression in both isolated skeletal fibers and extracts derived from whole FDB muscles. ATP increased IL-6 release up to 10-fold. STAT3 activation evoked by ATP was abolished by the JAK2 inhibitor HBC. Blockade of secreted IL-6 with a neutralizing antibody or preincubation with the STAT3 inhibitor VIII reduced STAT3 activation evoked by extracellular ATP by 70%. Inhibitor VIII also reduced by 70% IL-6 expression evoked by ATP, suggesting a positive IL-6 loop. In addition, ATP increased up to 60% the protein levels of SOCS3, a negative regulator of the IL-6 signaling pathway. On the other hand, intracellular calcium chelation or blockade of IP3-dependent calcium signals abolished STAT3 phosphorylation evoked by either extracellular ATP or ES. These results suggest that expression of IL-6 in stimulated skeletal muscle cells is mediated by extracellular ATP and nucleotide receptors, involving IP3-dependent calcium signals as an early step that triggers a positive IL-6 autocrine loop.
Mario Bustamante; Rodrigo Fernández-Verdejo; Enrique Jaimovich; Sonja Buvinic. Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca2+ signals and an IL-6 autocrine loop. American Journal of Physiology-Endocrinology and Metabolism 2014, 306, E869 -E882.
AMA StyleMario Bustamante, Rodrigo Fernández-Verdejo, Enrique Jaimovich, Sonja Buvinic. Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca2+ signals and an IL-6 autocrine loop. American Journal of Physiology-Endocrinology and Metabolism. 2014; 306 (8):E869-E882.
Chicago/Turabian StyleMario Bustamante; Rodrigo Fernández-Verdejo; Enrique Jaimovich; Sonja Buvinic. 2014. "Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca2+ signals and an IL-6 autocrine loop." American Journal of Physiology-Endocrinology and Metabolism 306, no. 8: E869-E882.