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Featured researches published by Chenglin Mo.


Recent Patents on Biotechnology | 2012

Prostaglandin E2: From Clinical Applications to Its Potential Role in Bone- Muscle Crosstalk and Myogenic Differentiation

Chenglin Mo; Sandra Romero-Suarez; Lynda F. Bonewald; Mark R. Johnson; Marco Brotto

Prostaglandin E(2) (PGE(2)), a prostanoid synthesized from arachidonic acid via the cyclooxygenase pathway, is a modulator of physiological responses including inflammation, fever, and muscle regeneration. Several patents have been filed that are related to PGE(2), one of them being directly related to skeletal muscles. In this report, we first summarize the key patents describing inventions for the utilization of PGE(2) for either diagnostic or therapeutic purposes, including skeletal muscle. In the second part of our work we present new and exciting data that demonstrates that PGE(2) accelerates skeletal muscle myogenic differentiation. Our discovery resulted from our recent and novel concept of bone-muscle crosstalk. Bone and muscle are anatomically intimate endocrine organs and we aimed to determine whether this anatomical intimacy also translates into a biochemical communication from bone cells to muscle cells at the in vitro level. The effects of MLOY4 osteocyte-like cell conditioned medium (CM) and three osteocyte-secreted factors, PGE(2), sclerostin and monocyte chemotactic protein (MCP-3), on C2C12 myogenic differentiation were evaluated using morphological analyses, a customized 96-gene PCR array, and measurements of intracellular calcium levels. MLO-Y4 CM and PGE(2), but not sclerostin and MCP-3, induced acceleration of myogenesis of C2C12 myoblasts that was linked with significant modifications in intracellular calcium homeostasis. This finding should further stimulate the pursuit of new patents to explore the use of PGE(2) and the new concept of bone-muscle crosstalk for the development and application of inventions designed to treat muscle diseases characterized by enhanced muscle wasting, such as sarcopenia.


Journal of Bone and Mineral Research | 2014

METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-κB signaling pathway.

Jian Huang; Yi-Hsiang Hsu; Chenglin Mo; Eduardo Abreu; Douglas P. Kiel; Lynda F. Bonewald; Maxrco Brotto; David Karasik

Sarcopenia and osteoporosis are important public health problems that occur concurrently. A bivariate genome‐wide association study (GWAS) identified METTL21c as a suggestive pleiotropic gene for both bone and muscle. The METTL21 family of proteins methylates chaperones involved in the etiology of both myopathy and inclusion body myositis with Pagets disease. To validate these GWAS results, Mettl21c mRNA expression was reduced with siRNA in a mouse myogenic C2C12 cell line and the mouse osteocyte‐like cell line MLO‐Y4. At day 3, as C2C12 myoblasts start to differentiate into myotubes, a significant reduction in the number of myocytes aligning/organizing for fusion was observed in the siRNA‐treated cells. At day 5, both fewer and smaller myotubes were observed in the siRNA‐treated cells as confirmed by histomorphometric analyses and immunostaining with myosin heavy chain (MHC) antibody, which only stains myocytes/myotubes but not myoblasts. Intracellular calcium (Ca2+) measurements of the siRNA‐treated myotubes showed a decrease in maximal amplitude peak response to caffeine, suggesting that less Ca2+ is available for release due to the partial silencing of Mettl21c, correlating with impaired myogenesis. In siRNA‐treated MLO‐Y4 cells, 48 hours after treatment with dexamethasone there was a significant increase in cell death, suggesting a role of Mettl21c in osteocyte survival. To investigate the molecular signaling machinery induced by the partial silencing of Mettl21c, we used a real‐time PCR gene array to monitor the activity of 10 signaling pathways. We discovered that Mettl21c knockdown modulated only the NF‐κB signaling pathway (ie, Birc3, Ccl5, and Tnf). These results suggest that Mettl21c might exert its bone‐muscle pleiotropic function via the regulation of the NF‐κB signaling pathway, which is critical for bone and muscle homeostasis. These studies also provide rationale for cellular and molecular validation of GWAS, and warrant additional in vitro and in vivo studies to advance our understanding of role of METTL21C in musculoskeletal biology.


Cell Cycle | 2015

Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation

Chenglin Mo; Ruonan Zhao; Julian Vallejo; Orisa J. Igwe; Lynda F. Bonewald; Lori Wetmore; Marco Brotto

We recently demonstrated that conditioned media (CM) from osteocytes enhances myogenic differentiation of myoblasts, suggesting that signaling from bone may be important for skeletal muscle myogenesis. The effect of CM was closely mimicked by prostaglandin E2 (PGE2), a bioactive lipid mediator in various physiological or pathological conditions. PGE2 is secreted at high levels by osteocytes and such secretion is further enhanced under loading conditions. Although four types of receptors, EP1 to EP4, mediate PGE2 signaling, it is unknown whether these receptors play a role in myogenesis. Therefore, in this study, the expression of EPs in mouse primary myoblasts was characterized, followed by examination of their roles in myoblast proliferation by treating myoblasts with PGE2 or specific agonists. All four PGE2 receptor mRNAs were detectable by quantitative real-time PCR (qPCR), but only PGE2 and EP4 agonist CAY 10598 significantly enhance myoblast proliferation. EP1/EP3 agonist 17-phenyl trinor PGE2 (17-PT PGE2) and EP2 agonist butaprost did not have any significant effects. Moreover, treatment with EP4 antagonist L161,982 dose-dependently inhibited myoblast proliferation. These results were confirmed by cell cycle analysis and the gene expression of cell cycle regulators. Concomitant with the inhibition of myoblast proliferation, treatment with L161,982 significantly increased intracellular reactive oxygen species (ROS) levels. Cotreatment with antioxidant N-acetyl cysteine (NAC) or sodium ascorbate (SA) successfully reversed the inhibition of myoblast proliferation and ROS overproduction caused by L161,982. Therefore, PGE2 signaling via the EP4 receptor regulates myogenesis by promoting myoblast proliferation and blocking this receptor results in increased ROS production in myoblasts.


Journal of Biological Chemistry | 2016

Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age.

Jeff P. Gorski; Nichole T. Huffman; Julian Vallejo; Leticia Brotto; Sridar V. Chittur; Anne Breggia; Amber Rath Stern; Jian Huang; Chenglin Mo; Nabil G. Seidah; Lynda F. Bonewald; Marco Brotto

Conditional deletion of Mbtps1 (cKO) protease in bone osteocytes leads to an age-related increase in mass (12%) and in contractile force (30%) in adult slow twitch soleus muscles (SOL) with no effect on fast twitch extensor digitorum longus muscles. Surprisingly, bone from 10–12-month-old cKO animals was indistinguishable from controls in size, density, and morphology except for a 25% increase in stiffness. cKO SOL exhibited increased expression of Pax7, Myog, Myod1, Notch, and Myh3 and 6-fold more centralized nuclei, characteristics of postnatal regenerating muscle, but only in type I myosin heavy chain-expressing cells. Increased expression of gene pathways mediating EGF receptor signaling, circadian exercise, striated muscle contraction, and lipid and carbohydrate oxidative metabolism were also observed in cKO SOL. This muscle phenotype was not observed in 3-month-old mice. Although Mbtps1 mRNA and protein expression was reduced in cKO bone osteocytes, no differences in Mbtps1 or cre recombinase expression were observed in cKO SOL, explaining this age-related phenotype. Understanding bone-muscle cross-talk may provide a fresh and novel approach to prevention and treatment of age-related muscle loss.


JBMR Plus | 2017

Crosstalk Between MLO-Y4 Osteocytes and C2C12 Muscle Cells Is Mediated by the Wnt/β-Catenin Pathway: WNT/β-CATENIN PATHWAY MEDIATES OSTEOCYTES AND MUSCLE CELLS CROSSTALK

Jian Huang; Sandra Romero-Suarez; N. Lara; Chenglin Mo; Simon Kaja; Leticia Brotto; Sarah L. Dallas; Mark L. Johnson; Katharina Jähn; Lynda F. Bonewald; Marco Brotto

We examined the effects of osteocyte secreted factors on myogenesis and muscle function. MLO‐Y4 osteocyte‐like cell conditioned media (CM) (10%) increased ex vivo soleus muscle contractile force by ∼25%. MLO‐Y4 and primary osteocyte CM (1% to 10%) stimulated myogenic differentiation of C2C12 myoblasts, but 10% osteoblast CMs did not enhance C2C12 cell differentiation. Because WNT3a and WNT1 are secreted by osteocytes, and the expression level of Wnt3a is increased in MLO‐Y4 cells by fluid flow shear stress, both were compared, showing WNT3a more potent than WNT1 in inducing myogenesis. Treatment of C2C12 myoblasts with WNT3a at concentrations as low as 0.5 ng/mL mirrored the effects of both primary osteocyte and MLO‐Y4 CM by inducing nuclear translocation of β‐catenin with myogenic differentiation, suggesting that Wnts might be potential factors secreted by osteocytes that signal to muscle cells. Knocking down Wnt3a in MLO‐Y4 osteocytes inhibited the effect of CM on C2C12 myogenic differentiation. Sclerostin (100 ng/mL) inhibited both the effects of MLO‐Y4 CM and WNT3a on C2C12 cell differentiation. RT‐PCR array results supported the activation of the Wnt/β‐catenin pathway by MLO‐Y4 CM and WNT3a. These results were confirmed by qPCR, showing upregulation of myogenic markers and two Wnt/β‐catenin downstream genes, Numb and Flh1. We postulated that MLO‐Y4 CM/WNT3a could modulate intracellular calcium homeostasis as the trigger mechanism for the enhanced myogenesis and contractile force. MLO‐Y4 CM and WNT3a increased caffeine‐induced Ca2+ release from the sarcoplasmic reticulum (SR) of C2C12 myotubes and the expression of genes directly associated with intracellular Ca2+ signaling and homeostasis. Together, these data show that in vitro and ex vivo, osteocytes can stimulate myogenesis and enhance muscle contractile function and suggest that Wnts could be mediators of bone to muscle signaling, likely via modulation of intracellular Ca2+ signaling and the Wnt/ β‐Catenin pathway.


Recent Patents on Biotechnology | 2013

A Dual Mode Pulsed Electro-Magnetic Cell Stimulator Produces Acceleration of Myogenic Differentiation

Walter D. Leon-Salas; Hatem Ibrahim Rizk; Chenglin Mo; Noah Weisleder; Leticia Brotto; Eduardo Abreu; Marco Brotto

This paper presents the design and test of a dual-mode electric and magnetic biological stimulator (EM-Stim). The stimulator generates pulsing electric and magnetic fields at programmable rates and intensities. While electric and magnetic stimulators have been reported before, this is the first device that combines both modalities. The ability of the dual stimulation to target bone and muscle tissue simultaneously has the potential to improve the therapeutic treatment of osteoporosis and sarcopenia. The device is fully programmable, portable and easy to use, and can run from a battery or a power supply. The device can generate magnetic fields of up to 1.6 mT and output voltages of +/- 40 V. The EM-Stim accelerated myogenic differentiation of myoblasts into myotubes as evidenced by morphometric, gene expression, and protein content analyses. Currently, there are many patents concerned with the application of single electrical or magnetic stimulation, but none that combine both simultaneously. However, we applied for and obtained a provisional patent for new device to fully explore its therapeutic potential in pre-clinical models.


Recent Patents on Biotechnology | 2012

Jatropha curcas: From Biodiesel Generation to Medicinal Applications

Luis Paulillo; Chenglin Mo; Janalee Isaacson; Luciene Lessa; Edjacy Lopes; Sandra Romero-Suarez; Leticia Brotto; Eduardo Abreu; William G. Gutheil; Marco Brotto

Jatropha curcas (JC) is a multipurpose perennial plant that belongs to the Euphorbiaceae family and is native to arid and semiarid tropical regions worldwide. It has many attributes and considerable potential for renewable energy, fish and livestock feeding. Despite its rich application as a renewable source and for animal feeding, JC has barely been explored for its medicinal potential. Here we review several patents related to JC that show it has been underused for medicinal purposes. For example, only one invention disclosure to date utilizes JC, combined with three other plants, in a preparation for wound healing. Motivated by support from the Brazilian funding agencies and anecdotal accounts in Brazil of the medicinal value of JC, we performed a series of pilot studies that demonstrate that JC is able to protect skeletal muscle cells in vitro against the deleterious effects of ethanol. We were able to determine that JCs effects are mediated by the up regulation of HSP60, a critical mitochondrial heat shock related protein that is essential for intracellular REDOX regulation. Given the fact that ethanol myopathy accounts for more than 50% of all cases of myopathy worldwide, we hope that our studies will sparkle new interest from the scientific community to explore the medicinal properties of Jatropha curcas, including the development of new patents leading to new drugs and new targets for the treatment of muscle diseases and other human diseases.


Recent Patents on Biotechnology | 2012

Hyperthermia: from diagnostic and treatments to new discoveries.

Sandra Romero-Suarez; Chenglin Mo; Chad D. Touchberry; Nuria Lara; Kendra Baker; Robin Craig; Leticia Brotto; Jon Andresen; Michael J. Wacker; Simon Kaja; Eduardo Abreu; Wolfgang H. Dillmann; Ruben Mestril; Marco Brotto; Thomas M. Nosek

Hyperthermia is an important approach for the treatment of several diseases. Hyperthermia is also thought to induce hypertrophy of skeletal muscles in vitro and in vivo, and has been used as a therapeutic tool for millennia. In the first part of our work, we revise several relevant patents related to the utilization of hyperthermia for the treatment and diagnostic of human diseases. In the second part, we present exciting new data on the effects of forced and natural overexpression of HSP72, using murine in vitro (muscle cells) and ex vivo (primary skeletal muscles) models. These studies help to demonstrate that hyperthermia effects are orchestrated by tight coupling between gene expression, protein function, and intracellular Ca2+ signaling pathways with a key role for calcium-induced calcium release. We hope that the review of current patents along with previous unknown information on molecular signaling pathways that underlie the hypertrophy response to hyperthermia in skeletal muscles may trigger the curiosity of scientists worldwide to explore new inventions that fully utilize hyperthermia for the treatment of muscle diseases.


Archive | 2017

Bone and Muscle

Chenglin Mo; Zhiying Wang; Lynda F. Bonewald; Marco Brotto

Muscle and bone are anatomically integrated with each other to form the musculoskeletal system. Muscle has been considered as an endocrine organ to affect other tissues, including bone, via secreting factors within the microenvironment to modulate their biological functions. Thus muscle is essential for bone development, modeling, and remodeling. Similar to muscle, bone can also be considered an endocrine organ targeting other tissues such as muscle. Therefore, the aim of this chapter is to summarize endocrine factors derived from either bone or muscle and their potential benefits for the therapy of simultaneous bone-muscle dysfunction, such as osteoporosis and sarcopenia in the elderly population. Herein, we first describe the synchronous development of the musculoskeletal system during embryogenesis and how this close relationship between bone and muscle continues in postnatal life. Then the factors regulating both bone and muscle, including factors like myogenic regulatory factors (MRFs) and myostatin from muscle, bone-derived factors like bone morphogenetic proteins (BMPs) and prostaglandin E2 (PGE2), as well as other secretory factors, are discussed to provide a better understanding of the mechanisms underlying the parallel development of musculoskeletal system diseases. Finally, we discuss some meaningful and innovative treatment strategies, which preferentially strengthen the musculoskeletal unit as a whole.


European Cells & Materials | 2012

Skeletal muscle secreted factors prevent glucocorticoid-induced osteocyte apoptosis through activation of β-catenin.

Katharina Jähn; N. Lara-Castillo; Leticia Brotto; Chenglin Mo; Mark L. Johnson; Marco Brotto; Lynda F. Bonewald

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Marco Brotto

Case Western Reserve University

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Leticia Brotto

University of Missouri–Kansas City

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Lynda F. Bonewald

University of Missouri–Kansas City

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Eduardo Abreu

University of Missouri–Kansas City

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Jian Huang

University of Missouri–Kansas City

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Sandra Romero-Suarez

University of Missouri–Kansas City

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Janalee Isaacson

University of Missouri–Kansas City

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Julian Vallejo

University of Missouri–Kansas City

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Mark L. Johnson

University of Missouri–Kansas City

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Katharina Jähn

University of Missouri–Kansas City

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