Yi-Guo Yan

PI3K/Akt signaling in osteosarcoma.

Osteosarcoma (OS) is the most common nonhematologic bone malignancy in children and adolescents. Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis remains generally poor. As such, the search for more effective anti-OS agents is urgent. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is thought to be one of the most important oncogenic pathways in human cancer. An increasing body of evidence has shown that this pathway is frequently hyperactivated in OS and contributes to disease initiation and development, including tumorigenesis, proliferation, invasion, cell cycle progression, inhibition of apoptosis, angiogenesis, metastasis and chemoresistance. Inhibition of this pathway through small molecule compounds represents an attractive potential therapeutic approach for OS. The aim of this review is to summarize the roles of the PI3K/Akt pathway in the development and progression of OS, and to highlight the therapeutic potential of targeting this signaling pathway. Knowledge obtained from the application of these compounds will help in further understanding the pathogenesis of OS and designing subsequent treatment strategies.

MicroRNAs in osteosarcoma

Osteosarcoma (OS) is a primary malignant bone tumor with high morbidity that principally emerges in children and adolescents. Presently, the prognosis of OS patients remains poor due to resistance to chemotherapy, highlighting the need for new therapeutic approaches. MicroRNAs (miRNAs), a class of small noncoding RNA molecules, can negatively modulate protein expression at the post-transcriptional level. miRNAs regulate a variety of normal physiologic processes and are involved in tumorigenesis and development of multiple malignancies, including OS. Some miRNAs are differentially expressed in OS tissues, cell lines and serum, and have been shown to correlate with the malignant phenotype and prognosis. These altered miRNAs function as oncogenes or tumor suppressor genes in this process. Moreover, restoration of miRNA expression has shown promise for the treatment of OS. Here, we describe miRNA biochemistry with a focus on expression profile, role and therapeutic potential in OS. A better understanding will facilitate the identification and characterization of novel biomarkers and development of miRNA-targeted therapies.

MMPs and ADAMTSs in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with low back pain, a leading cause of musculoskeletal disability worldwide. The major components of extracellular matrix (ECM) within the discs are type II collagen (Col II) and aggrecan. Excessive destruction of ECM, especially loss of Col II and aggrecan, plays a critical role in promoting the occurrence and development of IDD. Matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTSs) are primary enzymes that degrade collagens and aggrecan. There is a large and growing body of evidence that many members of MMPs and ADAMTSs are highly expressed in degenerative IVD tissue and cells, and are closely involved in ECM breakdown and the process of disc degeneration. In contrast, targeting these enzymes has shown promise for promoting ECM repair and mitigating disc regeneration. In the current review, after a brief description regarding the biology of MMPs and ADAMTSs, we mainly focus on their expression profiles, roles and therapeutic potential in IDD. A greater understanding of the catabolic pathways involved in IDD will help to develop potential prophylactic or regenerative biological treatment for degenerative disc disease in the future.

Interleukin-1β in intervertebral disk degeneration.

Intervertebral disk degeneration (IDD) is the most common diagnosis in patients with low back pain, a main cause of musculoskeletal disability in the world. Interleukin-1 (IL-1) β is the most important member of the IL-1 family, and has a strong pro-inflammatory activity by stimulating the secretion of multiple pro-inflammatory mediators. IL-1β is highly expressed in degenerative intervertebral disk (IVD) tissues and cells, and it has been shown to be involved in multiple pathological processes during disk degeneration, including inflammatory responses, matrix destruction, angiogenesis and innervation, cellular apoptosis, oxidative stress and cellular senescence. However, inhibition of IL-1β is found to promote extracellular matrix (ECM) repair and protect against disk regeneration. In this review, after a brief description of IL-1β signaling, we mainly focus on the expression profiles, roles and therapeutic potential of IL-1β in IDD. A better understanding will help develop novel IL-1β-based therapeutic interventions for degenerative disk disease.

The PI3K/Akt pathway: a critical player in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future.Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future.

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Intervertebral disc (IVD) degeneration (IDD) is the most common cause leading to low back pain (LBP), which is a highly prevalent, costly, and crippling condition worldwide. Current treatments for IDD are limited to treat the symptoms and do not target the pathophysiology. Tumor necrosis factor-&agr; (TNF-&agr;) is one of the most potent pro-inflammatory cytokines and signals through its receptors TNFR1 and TNFR2. TNF-&agr; is highly expressed in degenerative IVD tissues, and it is deeply involved in multiple pathological processes of disc degeneration, including matrix destruction, inflammatory responses, apoptosis, autophagy, and cell proliferation. Importantly, anti-TNF-&agr; therapy has shown promise for mitigating disc degeneration and relieving LBP. In this review, following a brief description of TNF-&agr; signal transduction, we mainly focus on the expression pattern and roles of TNF-&agr; in IDD, and summarize the emerging progress regarding its inhibition as a promising biological therapeutic approach to disc degeneration and associated LBP. A better understanding will help to develop novel TNF-&agr;–centered therapeutic interventions for degenerative disc disease.

lncRNAs: novel players in intervertebral disc degeneration and osteoarthritis.

The term long non‐coding RNA (lncRNA) refers to a group of RNAs with length more than 200 nucleotides, limited protein‐coding potential, and having widespread biological functions, including regulation of transcriptional patterns and protein activity, formation of endogenous small interfering RNAs (siRNAs) and natural microRNA (miRNA) sponges. Intervertebral disc degeneration (IDD) and osteoarthritis (OA) are the most common chronic, prevalent and age‐related degenerative musculoskeletal disorders. Numbers of lncRNAs are differentially expressed in human degenerative nucleus pulposus tissue and OA cartilage. Moreover, some lncRNAs have been shown to be involved in multiple pathological processes during OA, including extracellular matrix (ECM) degradation, inflammatory responses, apoptosis and angiogenesis. In this review, we summarize current knowledge concerning lncRNAs, from their biogenesis, classification and biological functions to molecular mechanisms and therapeutic potential in IDD and OA.

Autophagy: A double-edged sword in intervertebral disk degeneration

Autophagy is a homeostatic mechanism through which intracellular damaged organelles and proteins are degraded and recycled in response to increased metabolic demands or stresses. Although primarily cytoprotective, dysfunction of autophagy is often associated with many degenerative diseases, including intervertebral disc (IVD) degeneration (IDD). As a main contributing factor to low back pain, IDD is the pathological basis for various debilitating spinal diseases. Either higher or lower levels of autophagy are observed in degenerative IVD cells. Despite the precise role of autophagy in disc degeneration that is still controversial, with difference from protection to aggravation, targeting autophagy has shown promise for mitigating disc degeneration. In the current review, we summarize the changes of autophagy in degenerative IVD cells and mainly discuss the relationship between autophagy and IDD. With continued efforts, modulation of the autophagic process could be a potential and attractive therapeutic strategy for degenerative disc disease.

MiR-210 facilitates ECM degradation by suppressing autophagy via silencing of ATG7 in human degenerated NP cells.

Intervertebral disc degeneration (IDD) is thought to be the most common cause of low back pain. Dysregulation of microRNAs (miRNAs) is involved in the development of IDD. The aim of this study was to explore the influence of miR-210 on type II collagen (Col II) and aggrecan expression and possible mechanisms in human degenerated nucleus pulposus (NP) cells. Our results showed that miR-210 levels were significantly increased in degenerated NP tissues compared with healthy controls, and positively correlated with disc degeneration grade. By gain-of-function and loss-of-function studies in human degenerated NP cells, miR-210 was shown to inhibit autophagy and then upregulate MMP-3 and MMP-13 expression, leading to increased degradation of Col II and aggrecan. Autophagy-related gene 7 (ATG7) was identified as a direct target of miR-210. Knockdown of ATG7 by small interfering RNA (siRNA) abrogated the effects of miR-210 inhibitor on MMP-3, MMP-13, Col II and aggrecan expression. Taken together, these results suggest that miR-210 inhibits autophagy via silencing of ATG7, leading to increased Col II and aggrecan degradation in human degenerated NP cells.

MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells

Intervertebral disc degeneration (IDD) is the most common cause leading to low back pain, a highly prevalent, costly and crippling condition worldwide. Overexpression of miR-21 has been shown to promote proliferation of nucleus pulposus (NP) cells. However, it remains unclear whether miR-21 can promote the degradation of type II collagen (Col II) and aggrecan, two main extracellular matrix components within the disc. Here, the miRNA microassay assay identified 29 differentially expressed miRNAs in NP tissues from IDD patients compared with healthy controls. Following qRT-PCR validation, miR-21 expression was significantly upregulated in degenerated NP tissues, and showed a positive correlation with disc degeneration grade. Through gain-of-function and loss-of-function studies in human NP cells, miR-21 was shown to inhibit autophagy and then upregulate the expression of matrix metalloproteinase (MMP)-3 and MMP-9, leading to increased degradation of Col II and aggrecan. Mechanistically, phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-21, and activated PTEN/ Akt/mammalian target of rapamycin (mTOR) signaling pathway was involved in miR-21-induced autophagy inhibition and Col II and aggrecan breakdown. Taken together, these results suggest that miR-21 contributes to Col II and aggrecan catabolism by inhibiting autophagy via the PTEN/Akt/mTOR signaling pathway in human NP cells.