Comparison of Kindlin-2 deficiency-stimulated osteoarthritis-like lesions induced by Prg4CreERT2 versus AggrecanCreERT2 transgene in mice

Yao, Qing1; Gong, Weiyuan1,3; Wu, Xiaohao1; Gan, Donghao1; Tao, Chu1; Lin, Sixiong2; Qu, Minghao1; Ouyang, Zhongtian1; Chen, Mingjue1; Hu, Xinjia3; Xiao, Guozhi1

2023-07-01

10.1016/j.jot.2023.05.005

JOURNAL OF ORTHOPAEDIC TRANSLATION   影响因子和分区

2214-031X

Background: Genetically modified mice are the most useful tools for investigating the gene functions in articular cartilage biology and the pathogenesis of osteoarthritis. The AggrecanCreERT2 mice are one of the most reported mouse lines used for this purpose. The Prg4 (proteoglycan 4) gene encodes the lubricin protein and is expressed selectively in chondrocytes located at the superficial layer of the articular cartilage. While the Prg4GFPCreERT2 knock-in inducible-Cre transgenic mice were generated a while ago, so far, few studies have used this mouse line to perform gene functional studies in cartilage biology.Methods: We have recently reported that deleting the Fermt2 gene, which encodes the key focal adhesion protein Kindlin-2, in articular chondrocytes by using the AggrecanCreERT2 transgenic mice, results in spontaneous osteo-arthritis (OA) lesions, which highly mimics the human OA pathologies. In this study, we have compared the Kindlin-2 deficiency-caused OA phenotypes induced by Prg4GFPCreERT2 with those caused by AggrecanCreERT2 using imaging and histological analyses.Results: We find that Kindlin-2 protein is deleted in about 75% of the superficial articular chondrocytes in the tamoxifen (TAM)-treated Prg4GFPCreERt2/+; Fermt2fl/fl mice compared to controls. At 6 months after TAM injections, the OARSI scores of AggrecanCreERT2/+; Fermt2fl/fl and Prg4GFPCreERt2/+; Fermt2fl/fl mice were 5 and 3, respectively. The knee joints histological osteophyte and synovitis scores were also significantly decreased in Prg4GFPCreERT2/+; Fermt2fl/fl mice compared to those in AggrecanCreERT2/+; Fermt2fl/fl mice. Furthermore, magnitudes of upregulation of the extracellular matrix-degrading enzymes Mmp13 and hypertrophic chondrocyte markers Col10a1 and Runx2 were decreased in Prg4GFPCreERT2/+; Fermt2fl/fl versus AggrecanCreERT2/+; Fermt2fl/fl mice. We finally exam-ined the susceptibility of Prg4GFPCreERT2/+; Fermt2fl/fl mouse model to surgically induce OA lesions. The patho-logical features of OA in the TAM-DMM model exhibited significant enhancement in cartilage erosion, proteoglycan loss, osteophyte, and synovitis and an increase in OARSI score in articular cartilage compared with those in corn-oil DMM mice.Conclusion: Kindlin-2 loss causes milder OA-like lesions in Prg4GFPCreERT2/+; Fermt2fl/fl than in AggrecanCreERT2/+; Fermt2fl/fl mice. In contrast, Kindlin-2 loss similarly accelerates the destabilization of the medial meniscus-induced OA lesions in both mice.Translational Potential of this Article: Our study demonstrates that Prg4GFPCreERT2 is a useful tool for gene functional study in OA research. This study provides useful information for investigators to choose appropriate Cre mouse lines for their research in cartilage biology.

Articular chondrocyte Osteoarthritis Kindlin-2 Prg4GFPCreERT2 AggrecanCreERT2

SCI

英语

第一 ; 通讯

National Key Research and Development Program of China[2019YFA0906004] ; National Natural Science Foundation of China["82230081","82250710175","81870532"] ; Shenzhen Stable Support Plan Program for Higher Education Institutions[2017B030301018] ; Shenzhen Key Basic Research and Development Program[82261160395] ; Shenzhen Key Laboratory of Cell Microenvironment Grant[82172375] ; Guangdong Provincial Science and Technology Innovation Council[81991513] ; null[20200925150409001] ; null[JCYJ20220818100617036] ; null[ZDSYS20140509142721429]

Orthopedics

Orthopedics

WOS:001013545600001

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Web of Science

1.Southern Univ Sci & Technol, Sch Med, Dept Biochem, Shenzhen Key Lab Cell Microenvironm,Guangdong Prov, Shenzhen 518055, Peoples R China
2.Sun Yat Sen Univ, Afiliated Hosp 1, Dept Spinal Surg, Guangdong Prov Key Lab Orthoped & Traumatol, Guangzhou 510080, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Dept Osteoarthropathy, Affiliated Hosp 1, Shenzhen 518035, Peoples R China

Yao, Qing,Gong, Weiyuan,Wu, Xiaohao,et al. Comparison of Kindlin-2 deficiency-stimulated osteoarthritis-like lesions induced by Prg4CreERT2 versus AggrecanCreERT2 transgene in mice[J]. JOURNAL OF ORTHOPAEDIC TRANSLATION,2023,41.

Yao, Qing.,Gong, Weiyuan.,Wu, Xiaohao.,Gan, Donghao.,Tao, Chu.,...&Xiao, Guozhi.(2023).Comparison of Kindlin-2 deficiency-stimulated osteoarthritis-like lesions induced by Prg4CreERT2 versus AggrecanCreERT2 transgene in mice.JOURNAL OF ORTHOPAEDIC TRANSLATION,41.

Yao, Qing,et al."Comparison of Kindlin-2 deficiency-stimulated osteoarthritis-like lesions induced by Prg4CreERT2 versus AggrecanCreERT2 transgene in mice".JOURNAL OF ORTHOPAEDIC TRANSLATION 41(2023).