Cbfβ Regulates Key Signaling Pathways to Maintain Articular Cartilage Homeostasis and Protect Against Osteoarthritis Development

Основные понятия

Cbfβ is a critical transcriptional regulator that maintains articular cartilage homeostasis by modulating Wnt/β-catenin, Hippo/Yap, and TGF-β signaling pathways. Deficiency of Cbfβ leads to spontaneous osteoarthritis development, while overexpression of Cbfβ protects against surgically-induced osteoarthritis.

Аннотация

The study investigates the role of Cbfβ, a subunit of the Cbfβ/Runx transcription factor complex, in regulating articular cartilage homeostasis and osteoarthritis (OA) pathogenesis.
Analysis of public human datasets showed that Cbfβ expression is decreased in the cartilage of OA patients compared to healthy individuals. Chondrocyte-specific deletion of Cbfβ in mice led to the development of a spontaneous OA phenotype, including worn articular cartilage, increased inflammation, and osteophyte formation.
RNA-sequencing analysis revealed that Cbfβ deficiency resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP and TGF-β signaling in articular cartilage. Immunostaining and western blot experiments validated these findings.
Further experiments showed that ACLT surgery-induced OA decreased Cbfβ and Yap expression while increasing active β-catenin expression in articular cartilage. Importantly, local AAV-mediated overexpression of Cbfβ promoted Yap expression and diminished active β-catenin expression in OA lesions, and significantly protected against articular cartilage damage in ACLT and DMM-induced OA mouse models.
The study demonstrates that Cbfβ is a critical regulator of articular cartilage homeostasis, and its deficiency leads to the activation of Wnt/β-catenin signaling, suppression of Hippo/Yap and TGF-β signaling, and ultimately the development of OA. Local overexpression of Cbfβ could be an effective therapeutic strategy for treating OA.

Статистика

Cbfβ mRNA expression is significantly decreased in cartilage of OA patients compared to healthy individuals.
Methylation at the Cbfβ promoter region is increased in hip tissue of OA patients compared to healthy individuals.
Cbfβ protein levels are significantly decreased in the articular cartilage of Cbfβf/fCol2α1-CreERT and Cbfβf/fAggrecan-CreERT mice after tamoxifen injection.
Cbfβf/fCol2α1-CreERT mice with ACLT surgery show more severe articular cartilage wear, joint space loss, hyperosteogeny, and increased subchondral bone density compared to control groups.
Cbfβf/fCol2α1-CreERT mice with no ACLT surgery have narrower knee joint space compared to WT mice with ACLT surgery.
AAV-mediated Cbfβ overexpression decreased active β-catenin expression by about 2.5-fold and increased Yap expression by about 3.5-fold in the knee joint articular cartilage of ACLT-induced OA mice.

Цитаты

"Cbfβ deficiency accelerated the development of OA in the Cbfβf/fCol2α1-CreERT mice with ACLT surgery."
"AAV-mediated Cbfβ overexpression protects against ACLT and DMM-induced OA in mice."
"Local overexpression of Cbfβ could be an effective therapeutic strategy for treating OA."

Ключевые выводы из

Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and TGFβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis

by Chen,W., Lu,... в www.biorxiv.org 01-16-2024

https://www.biorxiv.org/content/10.1101/2024.01.15.575763v1

Дополнительные вопросы

How might the tissue-specific regulation of Cbfβ in different joint tissues, such as hip versus knee, contribute to the heterogeneity of OA pathogenesis?

The tissue-specific regulation of Cbfβ in different joint tissues, such as the hip and knee, can contribute to the heterogeneity of OA pathogenesis through several mechanisms. Firstly, the differential expression of Cbfβ in these tissues may lead to variations in the activation of downstream signaling pathways involved in OA development. For example, the hip joint may have a higher expression of Cbfβ, leading to the maintenance of articular cartilage homeostasis, while the knee joint with lower Cbfβ expression may be more susceptible to cartilage degradation and OA progression.
Moreover, the distinct cellular composition and biomechanical stresses in the hip and knee joints can also influence the impact of Cbfβ deficiency on OA pathogenesis. The hip joint, with its unique structure and loading patterns, may respond differently to Cbfβ deletion compared to the knee joint. This differential response can result in varying degrees of cartilage damage, inflammation, and osteophyte formation, contributing to the heterogeneity of OA presentation in different joint tissues.
Additionally, the crosstalk between Cbfβ and other transcription factors or signaling molecules specific to each joint tissue can further modulate the OA pathogenesis. The interaction of Cbfβ with tissue-specific regulators of chondrocyte differentiation, inflammation, and matrix degradation can lead to tissue-specific alterations in gene expression and cellular responses, ultimately influencing the progression of OA in a joint-specific manner.

What are the potential upstream regulators of Cbfβ expression, and how could modulating these regulators be leveraged for OA treatment?

Several potential upstream regulators of Cbfβ expression include growth factors, cytokines, and transcription factors that are known to influence chondrocyte function and cartilage homeostasis. For example, TGF-β, BMPs, and Wnt signaling pathways have been implicated in the regulation of Cbfβ expression. These signaling molecules can activate specific transcription factors that directly or indirectly modulate Cbfβ expression in chondrocytes.
Modulating these upstream regulators of Cbfβ expression could be leveraged for OA treatment by targeting the signaling pathways that control Cbfβ levels. For instance, enhancing TGF-β or BMP signaling, which are known to upregulate Cbfβ expression, could potentially promote cartilage regeneration and repair in OA. Similarly, inhibiting Wnt signaling, which negatively regulates Cbfβ expression, may help prevent cartilage degradation and osteophyte formation in OA.
Furthermore, targeting specific transcription factors or epigenetic regulators that control Cbfβ expression could offer novel therapeutic strategies for OA treatment. By identifying and manipulating the factors that regulate Cbfβ expression, researchers and clinicians can potentially modulate the activity of Cbfβ and its downstream pathways to mitigate OA progression and promote joint health.

Given the complex interplay between Wnt, Hippo, and TGF-β signaling pathways, what other transcriptional or epigenetic mechanisms might Cbfβ employ to coordinate these pathways in maintaining articular cartilage homeostasis?

In addition to the direct regulation of Wnt, Hippo, and TGF-β signaling pathways, Cbfβ may employ other transcriptional or epigenetic mechanisms to coordinate these pathways in maintaining articular cartilage homeostasis. One potential mechanism is through the regulation of microRNAs (miRNAs) that target key components of these signaling pathways. Cbfβ could modulate the expression of specific miRNAs that fine-tune the activity of Wnt, Hippo, and TGF-β signaling cascades in chondrocytes.
Furthermore, Cbfβ may interact with chromatin remodeling complexes or histone modifiers to regulate the accessibility of key genes involved in these pathways. By influencing the epigenetic landscape of chondrocytes, Cbfβ can control the expression of genes critical for maintaining articular cartilage integrity and function.
Moreover, Cbfβ may engage in protein-protein interactions with other transcription factors or co-regulators to form transcriptional complexes that coordinate the activity of Wnt, Hippo, and TGF-β signaling pathways. These interactions can lead to synergistic or antagonistic effects on gene expression, ultimately shaping the cellular responses in articular cartilage and contributing to the maintenance of cartilage homeostasis.
Overall, the multifaceted role of Cbfβ in regulating transcriptional and epigenetic mechanisms underscores its importance in orchestrating the complex interplay between Wnt, Hippo, and TGF-β signaling pathways to ensure the proper function and health of articular cartilage.