Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction

Yang, Siyoung; Kim, Jonghwan; Ryu, Je‐Hwang; Oh, Han; Chun, Churl Hong; Kim, Byoung Ju; Min, Byoung Hyun; Chun, Jang‐Soo

doi:10.1038/nm.2153

Cited by 477 publications

(749 citation statements)

References 46 publications

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“…For the generation of chondrocyte-specific Dkk1-and Dkk2-transgenic mice, mouse Dkk1 and Dkk2 genes were cloned by polymerase chain reaction (PCR) using primers for Dkk1 (sense 5Ј-ATG-ATGGTTGTGTGTGCAGCGGCAGCT-3Ј and antisense 5Ј-TTAGTGTCTCTGGCAGGTGTGGA-3Ј) and Dkk2 (sense 5Ј-ATGGCCGCGCTGATGCGGGT-3Ј and antisense 5Ј-TCAGATCTTCTGGCATACATG-3Ј). The cloned complementary DNA (cDNA) was inserted into the Not I site of the pNass vector (Clontech), which contains the promoter and enhancer of the mouse Col2a1 gene (21). Animals were maintained under pathogen-free conditions.…”

Section: Methodsmentioning

confidence: 99%

“…Similar locations of the undamaged and damaged regions were selected for biochemical and histologic analysis. Human OA cartilage samples were frozen, sectioned at a thickness of 6 m, fixed in paraformaldehyde, and stained with Alcian blue (21).…”

Section: Methodsmentioning

confidence: 99%

“…Spontaneous OA cartilage destruction in STR/Ort mice was examined at age 28 weeks (21,24). Experimental OA was induced by destabilization of the medial meniscus (DMM) surgery or by intraarticular injection of 1 ϫ 10 9 plaque-forming units (PFU) of mouse Dkk1-expressing adenovirus (AdDkk-1) in 10-12-week-old male mice (21,25).…”

Section: Methodsmentioning

confidence: 99%

“…Experimental OA was induced by destabilization of the medial meniscus (DMM) surgery or by intraarticular injection of 1 ϫ 10 9 plaque-forming units (PFU) of mouse Dkk1-expressing adenovirus (AdDkk-1) in 10-12-week-old male mice (21,25). Sham-operated animals and animals injected with empty adenovirus (mock transduction) were used as controls for DMM and AdEPAS-1 injection models, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…We therefore addressed specific in vivo functions of Dkk-1 and Dkk-2 in OA cartilage destruction by using a Dkk1 and Dkk2 misexpression strategy. Specifically, we generated cartilage-specific Dkk1-and Dkk2-transgenic mice by using Col2a1 promoter and enhancer (21) to illustrate in vivo functions of Dkk-1 and Dkk-2 in OA pathogenesis. We report here that cartilagespecific overexpression of Dkk-1 exerts a protective effect in OA cartilage destruction by inhibiting the canonical Wnt pathway.…”

mentioning

confidence: 99%

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Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

Oh¹,

Chun²,

Chun³

2012

Arthritis & Rheumatism

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110

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Objective. Dkk is a family of canonical Wnt antagonists with 4 members (Dkk-1, Dkk-2, Dkk-3, and Dkk-4). We undertook this study to explore the roles of Dkk-1 and Dkk-2 in osteoarthritic (OA) cartilage destruction in mice.Methods. Expression of Dkk and other catabolic factors was determined at the messenger RNA and protein levels in human and mouse OA cartilage. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or by intraarticular injection of Epas1 adenovirus (AdEPAS-1). The role of Dkk in OA pathogenesis was examined by intraarticular injection of AdDkk-1 or by using chondrocyte-specific Dkk1 (Col2a1-Dkk1)-transgenic mice and Dkk2 (Col2a1-Dkk2)-transgenic mice. Primary culture mouse chondrocytes were also treated with recombinant Dkk proteins.Results. We found opposite patterns of Dkk1 and Dkk2 expression in human and mouse experimental OA cartilage: Dkk1 was up-regulated and Dkk2 was downregulated. Overexpression of Dkk1 by intraarticular injection of AdDkk-1 significantly inhibited DMMinduced experimental OA. DMM-induced OA was also significantly inhibited in Col2a1-Dkk1-transgenic mice compared with their wild-type littermates. However, Col2a1-Dkk2-transgenic mice showed no significant difference in OA pathogenesis. Wnt-3a, which activates the canonical Wnt pathway, induced Mmp13 and Adamts4 expression in primary culture chondrocytes, an effect that was significantly inhibited by Dkk-1 pretreatment or Dkk1 overexpression.Conclusion. Our findings indicate that expression of Dkk1, but not Dkk2, in chondrocytes inhibits OA cartilage destruction. The protective effect of Dkk-1 appears to be associated with its capacity to inhibit Wnt-mediated expression of catabolic factors, such as Mmp13, providing evidence that Dkk-1 might serve as a therapeutic target for OA treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

Oh¹,

Chun²,

Chun³

2012

Arthritis & Rheumatism

Self Cite

110

View full text Add to dashboard Cite

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Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

Majumder

Ghosh

2023

Adv Funct Materials

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Successful recapitulation of the anatomical microarchitecture and biomechanics of the native articular cartilage under in vitro culture conditions is still an elusive topic of research. The major roadblock lies in maintaining the stable chondrogenic phenotype in vivo or under long‐term in vitro conditions. Tissue engineers worldwide has coined this aberrant loss of permanent cartilage characteristics to transient cartilage form as “chondrocyte hypertrophy”. Although the following has been validated through the expression of a few known markers but very little is understood regarding the molecular mechanism that dwells underneath. This review summarizes the precise aetiology behind the development and progression of the hypertrophic phenotype in chondrocytes under in vitro chondrogenic conditions. Based on the current literature survey, it is deciphered that the type of cell utilized (chondrocytes or stem cells), the chondrogenic culture conditions (growth factors/biochemical mediators) and the culture microenvironment (oxygen tension, mechanical loading) during chondrogenesis have a direct correlation with the dysregulated activity of the chondrogenic signaling pathways corroborating the onset of hypertrophic maturation of chondrocytes. Furthermore, it is critically analyzed whether to completely inhibit these hypertrophy‐inducing signaling pathways or apply a brake in terms of time‐dependent dose due to their functional duality role in chondrogenesis.

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Overcoming the Dependence on Animal Models for Osteoarthritis Therapeutics – The Promises and Prospects of In Vitro Models

Singh

Moses

Bhardwaj

et al. 2021

Adv Healthcare Materials

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Osteoarthritis (OA) is a musculoskeletal disease characterized by progressive degeneration of osteochondral tissues. Current treatment is restricted to the reduction of pain and loss of function of the joint. To better comprehend the OA pathophysiological conditions, several models are employed, however; there is no consensus on a suitable model. In this review, different in vitro models being developed for possible therapeutic intervention of OA are outlined. Herein, various in vitro OA models starting from 2D model, co-culture model, 3D models, dynamic culture model to advanced technologies-based models such as 3D bioprinting, bioassembly, organoids, and organ-on-chip-based models are discussed with their advantages and disadvantages. Besides, different growth factors, cytokines, and chemicals being utilized for induction of OA condition are reviewed in detail. Furthermore, there is focus on scrutinizing different molecular and possible therapeutic targets for better understanding the mechanisms and OA therapeutics. Finally, the underlying challenges associated with in vitro models are discussed followed by future prospective. Taken together, a comprehensive overview of in vitro OA models, factors to induce OA-like conditions, and intricate molecular targets with the potential to develop personalized osteoarthritis therapeutics in the future with clinical translation is provided.

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Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction

Cited by 477 publications

References 46 publications

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

Overcoming the Dependence on Animal Models for Osteoarthritis Therapeutics – The Promises and Prospects of In Vitro Models

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