LncRNA SNHG1 modulates p38 MAPK pathway through Nedd4 and thus inhibits osteogenic differentiation of bone marrow mesenchymal stem cells. 2019

Yunpeng Jiang, and Wenliang Wu, and Guangjun Jiao, and Yunzhen Chen, and Haichun Liu
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250000, Shandong, China.

OBJECTIVE Current study aimed to investigate the effects of lncRNA SNHG1 on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explore the underlying mechanisms. METHODS Mouse model of osteoporosis was created by ovariectomy (OVX). The BMD of mice spine, the serum level of β-CTX and the ALP activity were measured. The expression of SNHG1, JNK, p-JNK, p-38, p-p38 and Osterix were examined by qRT-PCR and Western blot. Co-IP assay was used to verify the effect of SNHG1 on the interaction between p-p38 and Nedd4. Ubiquitination assay was used to evaluate the roles of SNHG1 in ubiquitination of p-p38. RESULTS In the mice with osteoporosis, BMD was decreased and β-CTX concentration and SNHG1 expression were increased. ALP activity and p-p38 protein level were elevated and SNHG1 expression was down-regulated in BMSCs stimulated by osteogenic inducer, while the effects were reversed by SNHG1 over-expression. SNHG1 over-expression enhanced the interaction between Nedd4 and p-p38, disrupted protein stability of p-p38, and promoted the ubiquitination of p-p38. In addition, pcDNA-SNHG1 down-regulated p-p38 protein level, and sh-Nedd4 removed the trend. Nedd4 silencing elevated ALP activity and Osterix protein level, while p-38 inhibitor abrogated the effects. In vivo, SNHG1 silence increased BMD and Osterix protein level, and decreased endogenous SNHG1 expression in mice with OVX. CONCLUSIONS This study proved the regulation mechanism that lncRNA SNHG1 negatively regulates p38 MAPK signal pathway through ubiquitination mediated by Nedd4, and thus inhibits osteogenic differentiation of BMSCs.

UI MeSH Term Description Entries
D010012 Osteogenesis The process of bone formation. Histogenesis of bone including ossification. Bone Formation,Ossification, Physiologic,Endochondral Ossification,Ossification,Ossification, Physiological,Osteoclastogenesis,Physiologic Ossification,Endochondral Ossifications,Ossification, Endochondral,Ossifications,Ossifications, Endochondral,Osteoclastogeneses,Physiological Ossification
D010024 Osteoporosis Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis (OSTEOPOROSIS, POSTMENOPAUSAL) and age-related or senile osteoporosis. Age-Related Osteoporosis,Bone Loss, Age-Related,Osteoporosis, Age-Related,Osteoporosis, Post-Traumatic,Osteoporosis, Senile,Senile Osteoporosis,Osteoporosis, Involutional,Age Related Osteoporosis,Age-Related Bone Loss,Age-Related Bone Losses,Age-Related Osteoporoses,Bone Loss, Age Related,Bone Losses, Age-Related,Osteoporoses,Osteoporoses, Age-Related,Osteoporoses, Senile,Osteoporosis, Age Related,Osteoporosis, Post Traumatic,Post-Traumatic Osteoporoses,Post-Traumatic Osteoporosis,Senile Osteoporoses
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005260 Female Females
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D000075702 Nedd4 Ubiquitin Protein Ligases E3 ubiquitin ligases that consist of four WW DOMAINS. They accept UBIQUITIN from E2 UBIQUITIN-CONJUGATING ENZYME as a thioester via their C-terminal HECT domains and transfer it specifically to the 63rd LYSINE residue (Lys-63) of target proteins. NEDD4 targets include many proteins and receptors with important functions for cell growth and homeostasis such as VEGFR-2; FGFR1 TYROSINE KINASE; and ERBB-4 RECEPTOR. They play a critical role in the internalization of these receptors, their degradation by LYSOSOMES, and also function as part of the ESCRT complex in VIRUS RELEASE. Nedd4 Proteins,Neuronal Precursor Cell-Expressed Developmentally Down-Regulated 4 Ligase,Neuronal Precursor Cell Expressed Developmentally Down Regulated 4 Ligase
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D048051 p38 Mitogen-Activated Protein Kinases A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens. Mitogen-Activated Protein Kinase p38,p38 Mitogen-Activated Protein Kinase,p38 MAP Kinase,p38 MAPK,p38 Protein Kinase,p38 SAPK,MAP Kinase, p38,MAPK, p38,Mitogen Activated Protein Kinase p38,Protein Kinase, p38,p38 Mitogen Activated Protein Kinase,p38 Mitogen Activated Protein Kinases

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