Therapeutic Approach For Osteoarthritis Research Articles

Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway.

Osteoarthritis (OA) is characterized by degradation of chondrocyte extracellular matrix (ECM). Accumulating evidence suggests that microRNAs (miRNAs) are associated with OA, but little is known of their function in chondrocyte ECM degradation. The objective of this study was to investigate the expression and function of miRNAs in OA. miRNA expression profile was determined in OA cartilage tissues and controls, employing Solexa sequencing and reverse transcription quantitative PCR (RT-qPCR). According to a modified Mankin scale, cartilage degradation was evaluated. Functional analysis of the miRNAs on chondrocyte ECM degradation was performed after miRNA transfection and IL-1β treatment. Luciferase reporter assays and western blotting were employed to determine miRNA targets. Expression of miR-221-3p was downregulated in OA cartilage tissues, which was significantly correlated with a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-221-3p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28I2 cells, SDF1 was identified as a target of miR-221-3p. SDF1 overexpression resulted in increased expression of catabolic genes such as MMP-13 and ADAMTS-5 in response to IL-1β, but these effects were moderated by miR-221-3p. SDF1 treatment antagonized this effect, while knockdown of SDF1 by shSDF1 induced inhibitory effects on the expression of CXCR4 and its main target genes, similar to miR-221-3p. The results indicate that upregulation of miR-221-3p could prevent IL-1β-induced ECM degradation in chondrocytes. Targeting the SDF1/CXCR4 signaling pathway may be used as a therapeutic approach for OA. miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis. KEY MESSAGES: miR-221-3p is downregulated in human cartilage tissues. miR-221-3p levels are associated with cartilage degeneration grade. miR-221-3p upregulation prevents IL-1β-induced ECM degradation in chondrocytes. Protection of ECM degradation by miR-223-3p occurs via SDF1/CXCR4 signaling. miR-221-3p is identified as a novel potential therapeutic target for osteoarthritis.

Knockdown of TREM-1 suppresses IL-1β-induced chondrocyte injury via inhibiting the NF-κB pathway

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently discovered molecule that modulates inflammatory responses. This study aimed to investigate the specific function of TREM-1 in chondrocytes and its association with the pathophysiology of osteoarthritis (OA). We observed upregulation of TREM-1 in OA cartilage compared to normal tissues. Knockdown of TREM-1 suppressed interleukin 1 beta (IL-1β)-induced extracellular matrix (ECM) metabolic imbalance, pro-inflammatory cytokine production, decrease in cell viability and apoptosis. Mechanistic analyses further revealed that IL-1β-induced activation of the NF-κB pathway is suppressed upon TREM-1 knockdown, similar to the effect of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. TREM-1 expression was consistently increased in a mouse OA model in vivo, and its silencing led to inhibition of matrix metallopeptidase-13 (MMP-13) production, increased collagen type II synthesis and decreased NF-κB signaling. Our data collectively suggest that TREM-1 plays a critical in OA development through regulation of NF-κB signaling. Pharmacological inhibition of TREM-1 may therefore present an effective novel therapeutic approach for OA.

Involvement of the endocannabinoid system in osteoarthritis pain

Osteoarthritis is a degenerative joint disease associated with articular cartilage degradation. The major clinical outcome of osteoarthritis is a complex pain state that includes both nociceptive and neuropathic mechanisms. Currently, the therapeutic approaches for osteoarthritis are limited as no drugs are available to control the disease progression and the analgesic treatment has restricted efficacy. Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for osteoarthritis pain. Indeed, pharmacological studies have shown the anti-nociceptive effects of cannabinoids in different rodent models of osteoarthritis, and compelling evidence suggests an active participation of the endocannabinoid system in the pathophysiology of this disease. The ubiquitous distribution of cannabinoid receptors, together with the physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function further support the therapeutic interest of cannabinoids for osteoarthritis. However, limited clinical evidence has been provided to support this therapeutic use of cannabinoids, despite the promising preclinical data. This review summarizes the promising results that have been recently obtained in support of the therapeutic value of cannabinoids for osteoarthritis management.

Biomechanical factors in osteoarthritis

Biomechanical factors play an important role in the health of diarthrodial joints. Altered joint loading - associated to obesity, malalignment, trauma or joint instability - is a critical risk factor for joint degeneration, whereas exercise and weight loss have generally been shown to promote beneficial effects for osteoarthritic joints. The mechanisms by which mechanical stress alters the physiology or pathophysiology of articular cartilage or other joint tissues likely involve complex interactions with genetic and molecular influences, particularly local or systemic inflammation secondary to injury or obesity. Chondrocytes perceive physical signals from their environment using a variety of mechanisms, including ion channels, integrin-mediated connections to the extracellular matrix that involve membrane, cytoskeletal and intracellular deformation. An improved understanding of the biophysical and molecular pathways involved in chondrocyte mechanotransduction can provide insight into the development of novel therapeutic approaches for osteoarthritis.

Aberrant hypertrophy in Smad3‐deficient murine chondrocytes is rescued by restoring transforming growth factor β–activated kinase 1/activating transcription factor 2 signaling: A potential clinical implication for osteoarthritis

AbstractObjectiveTo investigate the biologic significance of Smad3 in the progression of osteoarthritis (OA), the crosstalk between Smad3 and activating transcription factor 2 (ATF‐2) in the transforming growth factor β (TGFβ) signaling pathway, and the effects of ATF‐2 overexpression and p38 activation in chondrocyte differentiation.MethodsJoint disease in Smad3‐knockout (Smad3−/−) mice was examined by microfocal computed tomography and histologic analysis. Numerous in vitro methods including immunostaining, real‐time polymerase chain reaction, Western blotting, an ATF‐2 DNA‐binding assay, and a p38 kinase activity assay were used to study the various signaling responses and protein interactions underlying the altered chondrocyte phenotype in Smad3−/− mice.ResultsIn Smad3−/− mice, an end‐stage OA phenotype gradually developed. TGFβ‐activated kinase 1 (TAK1)/ATF‐2 signaling was disrupted in Smad3−/− mouse chondrocytes at the level of p38 MAP kinase (MAPK) activation, resulting in reduced ATF‐2 phosphorylation and transcriptional activity. Reintroduction of Smad3 into Smad3−/− cells restored the normal p38 response to TGFβ. Phosphorylated p38 formed a complex with Smad3 by binding to a portion of Smad3 containing both the MAD homology 1 and linker domains. Additionally, Smad3 inhibited the dephosphorylation of p38 by MAPK phosphatase 1 (MKP‐1). Both ATF‐2 overexpression and p38 activation repressed type X collagen expression in wild‐type and Smad3−/− chondrocytes. P38 was detected in articular cartilage and perichondrium; articular and sternal chondrocytes expressed p38 isoforms α, β, and γ, but not δ.ConclusionSmad3 is involved in both the onset and progression of OA. Loss of Smad3 abrogates TAK1/ATF‐2 signaling, most likely by disrupting the Smad3–phosphorylated p38 complex, thereby promoting p38 dephosphorylation and inactivation by MKP‐1. ATF‐2 and p38 activation inhibit chondrocyte hypertrophy. Modulation of p38 isoform activity may provide a new therapeutic approach for OA.

Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction.

Degradation of the collagenous extracellular matrix by metalloproteases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). Recently, it was suggested that endothelin 1 (ET-1), a potent vasoconstrictor, may be involved in MMP regulation. This study investigated the role of ET-1 in OA cartilage degradation. We explored ET-1 expression and synthesis in normal and OA cartilage and synovial membrane by reverse transcription-polymerase chain reaction and immunohistochemistry. MMP-1 and MMP-13 gene expression and protein synthesis were investigated using Northern blotting and enzyme-linked immunosorbent assays. Additionally, ET-1-induced collagenase activity, type II collagen metabolites, and tissue inhibitor of metalloproteases 1 (TIMP-1) protein were evaluated. We found expression and synthesis of ET-1, in situ, in both normal and OA cartilage and synovial membrane. We demonstrated that ET-1 induced gene expression and protein synthesis of both MMP-1 and MMP-13. These enzymes were produced in OA chondrocyte cultures, and the production increased in a dose-dependent manner in the presence of ET-1. In OA cartilage, ET-1 also induced type II collagen-derived neoepitopes concomitantly with an increase in collagenase activity and a decrease in TIMP-1 protein. Our results provide strong evidence of the catabolic role of ET-1 in OA cartilage via MMP-1 and MMP-13 up-regulation. As well, ET-1 increased the net MMP/TIMP balance and secondarily increased collagen degradation. Hence, ET-1 becomes an attractive factor to target in the conception of new therapeutic approaches for OA and other diseases in which MMP-13 and MMP-1 actions are crucial in tissue alteration.