SOXC Transcription Factors as Diagnostic Biomarkers and Therapeutic Targets for Arthritis

Ahmed, Emad A.; Alzahrani, Abdullah M.

doi:10.3390/ijms24044215

Cited by 10 publications

(5 citation statements)

References 49 publications

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“…Differential expression of Sox transcription factors in OA provides further support for a dual role of Sox transcription factors. Different Sox transcription factors may regulate GARR and Gdf5 in disparate ways: downregulation of Sox5/6/9 is associated with OA progression ( Lee and Im, 2011 ), while Sox4 and 11 are upregulated in OA ( Xu et al, 2019 ; Ahmed and Alzahrani, 2023 ). Thus, downregulation of Gdf5 in OA pathology implies Sox5/6/9 as positive regulators, whereas Sox4/11 are negative regulators of Gdf5.…”

Section: Discussionmentioning

confidence: 99%

Sox, Fox, and Lmx1b binding sites differentially regulate a Gdf5-Associated regulatory region during elbow development

Yeboah

Pira

Shankel

et al. 2023

Front. Cell Dev. Biol.

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Introduction: The articulating ends of limb bones have precise morphology and asymmetry that ensures proper joint function. Growth differentiation factor 5 (Gdf5) is a secreted morphogen involved in cartilage and bone development that contributes to the architecture of developing joints. Dysregulation of Gdf5 results in joint dysmorphogenesis often leading to progressive joint degeneration or osteoarthritis (OA). The transcription factors and cis-regulatory modules (CRMs) that regulate Gdf5 expression are not well characterized. We previously identified a Gdf5-associated regulatory region (GARR) that contains predicted binding sites for Lmx1b, Osr2, Fox, and the Sox transcription factors. These transcription factors are recognized factors involved in joint morphogenesis and skeletal development.Methods: We used in situ hybridization to Gdf5, Col2A1, and the transcription factors of interest in developing chicken limbs to determine potential overlap in expression. We further analyzed scRNA-seq data derived from limbs and knees in published mouse and chicken datasets, identifying cells with coexpression of Gdf5 and the transcription factors of interest. We also performed site-directed mutatgenesis of the predicted transcription factor binding sites in a GARR-reporter construct and determined any change in activity using targeted regional electroporation (TREP) in micromass and embryonic chicken wing bioassays.Results:Gdf5 expression overlapped the expression of these transcription factors during joint development both by in situ hybridization (ISH) and scRNA-seq analyses. Within the GARR CRM, mutation of two binding sites common to Fox and Sox transcripstion factors reduced enhancer activity to background levels in micromass cultures and in ovo embryonic chicken wing bioassays, whereas mutation of two Sox-only binding sites caused a significant increase in activity. These results indicate that the Fox/Sox binding sites are required for activity, while the Sox-only sites are involved in repression of activity. Mutation of Lmx1b binding sites in GARR caused an overall reduction in enhancer activity in vitro and a dorsal reduction in ovo. Despite a recognized role for Osr2 in joint development, disruption of the predicted Osr2 site did not alter GARR activity.Conclusion: Taken together, our data indicates that GARR integrates positive, repressive, and asymmetrical inputs to fine-tune the expression of Gdf5 during elbow joint development.

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Section: Discussionmentioning

confidence: 99%

Sox, Fox, and Lmx1b binding sites differentially regulate a Gdf5-Associated regulatory region during elbow development

Yeboah

Pira

Shankel

et al. 2023

Front. Cell Dev. Biol.

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“…In addition, TNF-α can inhibit the synthesis of cartilage matrix components, such as aggrecan and type II collagen, further impairing the structural integrity and function of the cartilage [57,58]. This effect on cartilage homeostasis further underscores the importance of TNF-α as a marker for assessing inflammation in chondrocytes.…”

Section: Creation Of Proinflammatory Chondrocyte Model and Its Evalua...mentioning

confidence: 99%

Efficient Generation of Chondrocytes From Bone Marrow–Derived Mesenchymal Stem Cells in a 3D Culture System: Protocol for a Practical Model for Assessing Anti-Inflammatory Therapies

Patnaik,

Jannati,

Sivani

et al. 2023

JMIR Res Protoc

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Background Chondrocytes are the primary cells responsible for maintaining cartilage integrity and function. Their role in cartilage homeostasis and response to inflammation is crucial for understanding the progression and potential therapeutic interventions for various cartilage-related disorders. Developing an accessible and cost-effective model to generate viable chondrocytes and to assess their response to different bioactive compounds can significantly advance our knowledge of cartilage biology and contribute to the discovery of novel therapeutic approaches. Objective We developed a novel, streamlined protocol for generating chondrocytes from bone marrow–derived mesenchymal stem cells (BMSCs) in a 3D culture system that offers significant implications for the study of cartilage biology and the discovery of potential therapeutic interventions for cartilage-related and associated disorders. Methods We developed a streamlined protocol for generating chondrocytes from BMSCs in a 3D culture system using an “in-tube” culture approach. This simple pellet-based 3D culture system allows for cell aggregation and spheroid formation, facilitating cell-cell and cell–extracellular matrix interactions that better mimic the in vivo cellular environment compared with 2D monolayer cultures. A proinflammatory chondrocyte model was created by treating the chondrocytes with lipopolysaccharide and was subsequently used to evaluate the anti-inflammatory effects of vitamin D, curcumin, and resveratrol. Results The established protocol successfully generated a large quantity of viable chondrocytes, characterized by alcian blue and toluidine blue staining, and demonstrated versatility in assessing the anti-inflammatory effects of various bioactive compounds. The chondrocytes exhibited reduced inflammation, as evidenced by the decreased tumor necrosis factor-α levels, in response to vitamin D, curcumin, and resveratrol treatment. Conclusions Our novel protocol offers an accessible and cost-effective approach for generating chondrocytes from BMSCs and for evaluating potential therapeutic leads in the context of inflammatory chondrocyte–related diseases. Although our approach has several advantages, further investigation is required to address its limitations, such as the potential differences between chondrocytes generated using our protocol and those derived from other established methods, and to refine the model for broader applicability and clinical translation.

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“…RA, on the other hand, is an autoimmune inflammatory disease that manifests as persistent and progressive synovitis, causing the formation of pannus that releases immunoglobulin and pro‐inflammatory factors to aggravate synovial inflammation and invade cartilage and bone 5,6 . Although important insights into the pathogenesis of these two diseases have been gained recently, 7,8 the concrete molecular mechanisms are still not fully elucidated, leading to a dearth of effective preventive and therapeutic strategies in clinical practice 9,10 …”

Section: Introductionmentioning

confidence: 99%

“…5,6 Although important insights into the pathogenesis of these two diseases have been gained recently, 7,8 the concrete molecular mechanisms are still not fully elucidated, leading to a dearth of effective preventive and therapeutic strategies in clinical practice. 9,10 Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are a pair of homologous transcriptional coactivators exhibiting strong structural similarities and genetic redundancy. They can sense and respond to alterations of mechanical cues both internally and externally, 11,12 and function in innate immunity and inflammation.…”

Section: Introductionmentioning

confidence: 99%

The role of YAP/TAZ on joint and arthritis

Lu,

Zhu,

et al. 2024

The FASEB Journal

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Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes‐associated protein (YAP) and its homolog transcriptional coactivator with PDZ‐binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords “YAP,” “TAZ,” “OA,” and “RA.”

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SOXC Transcription Factors as Diagnostic Biomarkers and Therapeutic Targets for Arthritis

Cited by 10 publications

References 49 publications

Sox, Fox, and Lmx1b binding sites differentially regulate a Gdf5-Associated regulatory region during elbow development

Sox, Fox, and Lmx1b binding sites differentially regulate a Gdf5-Associated regulatory region during elbow development

Efficient Generation of Chondrocytes From Bone Marrow–Derived Mesenchymal Stem Cells in a 3D Culture System: Protocol for a Practical Model for Assessing Anti-Inflammatory Therapies

The role of YAP/TAZ on joint and arthritis

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