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Editor-in-Chief | Osteoarthritis (OA) is a chronic degenerative joint disease, the most common in the elderly population, with high incidence and high disability
.
According to statistics, the incidence of knee OA is 33% in the population aged 60-70, and as high as 43.
7% in the population over the age of 80 [1]
.
OA can cause persistent joint pain and limited mobility, and can even lead to incapacitation in advanced stages
.
At present, because the molecular mechanism of the occurrence and development of OA disease is still not fully understood, there is no effective clinical drug for OA, and patients with advanced stage can only rely on joint replacement surgery to restore joint function, thus causing a huge social and economic burden
.
Articular cartilage degeneration is the most important pathological feature in the pathogenesis of OA, but its molecular mechanism is still not fully understood
.
Articular cartilage is rich in matrix components such as collagen and proteoglycans, which can provide buffering force for daily activities of joints
.
Chondrocytes are the only cell type within articular cartilage
.
During the stage of skeletal development, chondrocytes continue to proliferate, secrete matrix proteins, hypertrophic differentiation and apoptosis, providing a framework for subsequent skeletal formation
.
In adulthood, articular cartilage cells are in a relatively quiescent state
.
Recent studies have found that under the stimulation of pathological factors, articular chondrocytes undergo abnormal hypertrophy and differentiation and secrete matrix-degrading enzymes, leading to an imbalance of articular cartilage homeostasis and accelerating the occurrence and development of OA
.
Among them, key transcription factors such as Runx2 and Stat3 play an important role in promoting abnormal differentiation and catabolism of chondrocytes [2,3]
.
However, how articular chondrocytes inhibit their own hypertrophic differentiation and maintain matrix anabolism in physiological state, and whether abnormality of these processes in pathological state will lead to the occurrence and development of OA and its mechanism remain unclear
.
On February 10, 2022, Nature Aging published online the research work Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis
.
This study is the first to demonstrate the critical role of the focal adhesion protein Kindlin-2 in maintaining articular cartilage homeostasis: Loss of Kindlin-2 in adult mouse articular chondrocytes activates the Stat3-Runx2 pathway, stimulating abnormal chondrocyte hypertrophic differentiation and extracellular matrix catabolism, leading to spontaneous OA
.
The study also found that intra-articular injection of adeno-associated virus (AAV5-K2) expressing Kindlin-2 in mice can slow down the OA process caused by trauma or aging, providing new ideas and potential targets for clinical treatment of OA
.
Xiao Guozhi's team first reported the key role and mechanism of Kindlin-2 in skeletal development in 2015 [4]
.
During mouse development, deletion of Kindlin-2 from mesenchymal stem cells or chondrocytes causes severe skeletal dysplasia
.
However, it is unclear whether Kindlin-2 is expressed and functions in articular chondrocytes in adulthood
.
In this study, the team first found that Kindlin-2 is highly expressed in articular chondrocytes of healthy adult mice, and significantly decreased in articular chondrocytes of aging mice
.
To explore the potential role of Kindlin-2 in the regulation of articular chondrocyte homeostasis in adulthood, we constructed a tamoxifen-inducible chondrocyte Kindlin-2 knockout mouse model
.
Using this mouse model, the researchers found that the specific knockout of Kindlin-2 in adult mouse articular chondrocytes resulted in a severe spontaneous OA phenotype with pathological features including articular cartilage damage, subchondral sclerosis, synovial membrane Inflammation, pain, and osteophyte formation are highly similar to the pathological features of human OA
.
Meanwhile, in a destabilization of medial meniscus (DMM) model, the researchers found that the loss of Kindlin-2 in articular chondrocytes accelerated the occurrence and progression of DMM-induced OA
.
In terms of molecular mechanism, the team found that knockout of Kindlin-2 can activate the chondrocyte Stat3-Runx2 pathway, leading to abnormal hypertrophic differentiation of articular chondrocytes, extracellular matrix catabolism and the occurrence and development of OA
.
Examining cartilage samples from aging mice and patients with OA, the researchers found that downregulation of Kindlin-2 expression levels was highly correlated with abnormal upregulation of Stat3-Runx2 expression levels
.
The team further found that Kindlin-2 can exist in the mitochondria of chondrocytes.
Knockout of Kindlin-2 leads to the release of a large amount of reactive oxygen species (ROS) from the mitochondria of chondrocytes, and promotes the phosphorylation modification and nuclear transfer of Stat3.
.
In the cytoplasm, Kindlin-2 protein can directly bind to Stat3 protein to inhibit the phosphorylation activation of Stat3 by ROS
.
The team constructed two double-knockout mouse models (Stat3fl/fl; Kindlin-2fl/fl; AggrecanCreERT2 mouse model and Runx2fl/fl; Kindlin-2fl/fl; AggrecanCreERT2 mouse model), which confirmed the knockout in chondrocytes.
Either Stat3 or Runx2 gene can effectively alleviate cartilage degeneration and OA-like damage caused by the loss of Kindlin-2
.
Through the above experiments, the team confirmed that Kindlin-2 in chondrocytes can maintain chondrocyte homeostasis and combat the occurrence of OA by inhibiting the Stat3-Runx2 pathway
.
After elucidating the role and molecular mechanism of Kindlin-2 in physiological and pathological conditions, the team further explored the potential of treating OA by targeting the expression of Kindlin-2 in articular cartilage cells
.
The researchers used the previously established method of intra-articular injection of adeno-associated viruses serotype 5 (AAV5) to express exogenous Kindlin-2 protein in articular chondrocytes
.
The team found that injection of AAV expressing Kindlin-2 into the joint cavity of mice can significantly increase the expression level of Kindlin-2 protein in chondrocytes, and can slow down cartilage damage caused by DMM and delay the occurrence and development of aging OA, which is a clinical treatment.
OA provides new potential targets
.
In conclusion, this study clarifies the important role and molecular mechanism of Kindlin-2 in maintaining cartilage homeostasis by regulating the Stat3-Runx2 pathway, and provides new ideas and potential targets for clinical treatment of OA
.
Wu Xiaohao, a doctoral student at the School of Medicine of Southern University of Science and Technology, Lai Yumei, a teacher from the Department of Orthopedics at Rush University Medical Center, and Chen Sheng, a doctoral student at Tongji School of Medicine, Huazhong University of Science and Technology, are the co-first authors of the paper
.
Professor Xiao Guozhi, Associate Professor Cao Huiling from the School of Medicine of Southern University of Science and Technology, and Professor Bai Xiaochun from the School of Basic Medicine of Southern Medical University are the co-corresponding authors of the paper
.
Original link: https://doi.
org/10.
1038/s43587-021-00165-w Publisher: Eleven References 1.
Shane Anderson, A.
and RF Loeser, Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol, 2010.
24(1): p.
15-26.
2.
Chen, D.
, et al.
, Runx2 plays a central role in Osteoarthritis development.
J Orthop Translat, 2020.
23: p.
132-139.
3.
Latourte, A.
, et al.
, Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis.
Ann Rheum Dis, 2017.
76(4): p.
748-755.
4.
Wu, C.
, et al.
, Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis.
Nat Commun, 2015.
6: p.
7531.
Instructions for reprinting【Non-original article】The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
All legal rights, violators will be prosecuted
.
.
According to statistics, the incidence of knee OA is 33% in the population aged 60-70, and as high as 43.
7% in the population over the age of 80 [1]
.
OA can cause persistent joint pain and limited mobility, and can even lead to incapacitation in advanced stages
.
At present, because the molecular mechanism of the occurrence and development of OA disease is still not fully understood, there is no effective clinical drug for OA, and patients with advanced stage can only rely on joint replacement surgery to restore joint function, thus causing a huge social and economic burden
.
Articular cartilage degeneration is the most important pathological feature in the pathogenesis of OA, but its molecular mechanism is still not fully understood
.
Articular cartilage is rich in matrix components such as collagen and proteoglycans, which can provide buffering force for daily activities of joints
.
Chondrocytes are the only cell type within articular cartilage
.
During the stage of skeletal development, chondrocytes continue to proliferate, secrete matrix proteins, hypertrophic differentiation and apoptosis, providing a framework for subsequent skeletal formation
.
In adulthood, articular cartilage cells are in a relatively quiescent state
.
Recent studies have found that under the stimulation of pathological factors, articular chondrocytes undergo abnormal hypertrophy and differentiation and secrete matrix-degrading enzymes, leading to an imbalance of articular cartilage homeostasis and accelerating the occurrence and development of OA
.
Among them, key transcription factors such as Runx2 and Stat3 play an important role in promoting abnormal differentiation and catabolism of chondrocytes [2,3]
.
However, how articular chondrocytes inhibit their own hypertrophic differentiation and maintain matrix anabolism in physiological state, and whether abnormality of these processes in pathological state will lead to the occurrence and development of OA and its mechanism remain unclear
.
On February 10, 2022, Nature Aging published online the research work Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis
.
This study is the first to demonstrate the critical role of the focal adhesion protein Kindlin-2 in maintaining articular cartilage homeostasis: Loss of Kindlin-2 in adult mouse articular chondrocytes activates the Stat3-Runx2 pathway, stimulating abnormal chondrocyte hypertrophic differentiation and extracellular matrix catabolism, leading to spontaneous OA
.
The study also found that intra-articular injection of adeno-associated virus (AAV5-K2) expressing Kindlin-2 in mice can slow down the OA process caused by trauma or aging, providing new ideas and potential targets for clinical treatment of OA
.
Xiao Guozhi's team first reported the key role and mechanism of Kindlin-2 in skeletal development in 2015 [4]
.
During mouse development, deletion of Kindlin-2 from mesenchymal stem cells or chondrocytes causes severe skeletal dysplasia
.
However, it is unclear whether Kindlin-2 is expressed and functions in articular chondrocytes in adulthood
.
In this study, the team first found that Kindlin-2 is highly expressed in articular chondrocytes of healthy adult mice, and significantly decreased in articular chondrocytes of aging mice
.
To explore the potential role of Kindlin-2 in the regulation of articular chondrocyte homeostasis in adulthood, we constructed a tamoxifen-inducible chondrocyte Kindlin-2 knockout mouse model
.
Using this mouse model, the researchers found that the specific knockout of Kindlin-2 in adult mouse articular chondrocytes resulted in a severe spontaneous OA phenotype with pathological features including articular cartilage damage, subchondral sclerosis, synovial membrane Inflammation, pain, and osteophyte formation are highly similar to the pathological features of human OA
.
Meanwhile, in a destabilization of medial meniscus (DMM) model, the researchers found that the loss of Kindlin-2 in articular chondrocytes accelerated the occurrence and progression of DMM-induced OA
.
In terms of molecular mechanism, the team found that knockout of Kindlin-2 can activate the chondrocyte Stat3-Runx2 pathway, leading to abnormal hypertrophic differentiation of articular chondrocytes, extracellular matrix catabolism and the occurrence and development of OA
.
Examining cartilage samples from aging mice and patients with OA, the researchers found that downregulation of Kindlin-2 expression levels was highly correlated with abnormal upregulation of Stat3-Runx2 expression levels
.
The team further found that Kindlin-2 can exist in the mitochondria of chondrocytes.
Knockout of Kindlin-2 leads to the release of a large amount of reactive oxygen species (ROS) from the mitochondria of chondrocytes, and promotes the phosphorylation modification and nuclear transfer of Stat3.
.
In the cytoplasm, Kindlin-2 protein can directly bind to Stat3 protein to inhibit the phosphorylation activation of Stat3 by ROS
.
The team constructed two double-knockout mouse models (Stat3fl/fl; Kindlin-2fl/fl; AggrecanCreERT2 mouse model and Runx2fl/fl; Kindlin-2fl/fl; AggrecanCreERT2 mouse model), which confirmed the knockout in chondrocytes.
Either Stat3 or Runx2 gene can effectively alleviate cartilage degeneration and OA-like damage caused by the loss of Kindlin-2
.
Through the above experiments, the team confirmed that Kindlin-2 in chondrocytes can maintain chondrocyte homeostasis and combat the occurrence of OA by inhibiting the Stat3-Runx2 pathway
.
After elucidating the role and molecular mechanism of Kindlin-2 in physiological and pathological conditions, the team further explored the potential of treating OA by targeting the expression of Kindlin-2 in articular cartilage cells
.
The researchers used the previously established method of intra-articular injection of adeno-associated viruses serotype 5 (AAV5) to express exogenous Kindlin-2 protein in articular chondrocytes
.
The team found that injection of AAV expressing Kindlin-2 into the joint cavity of mice can significantly increase the expression level of Kindlin-2 protein in chondrocytes, and can slow down cartilage damage caused by DMM and delay the occurrence and development of aging OA, which is a clinical treatment.
OA provides new potential targets
.
In conclusion, this study clarifies the important role and molecular mechanism of Kindlin-2 in maintaining cartilage homeostasis by regulating the Stat3-Runx2 pathway, and provides new ideas and potential targets for clinical treatment of OA
.
Wu Xiaohao, a doctoral student at the School of Medicine of Southern University of Science and Technology, Lai Yumei, a teacher from the Department of Orthopedics at Rush University Medical Center, and Chen Sheng, a doctoral student at Tongji School of Medicine, Huazhong University of Science and Technology, are the co-first authors of the paper
.
Professor Xiao Guozhi, Associate Professor Cao Huiling from the School of Medicine of Southern University of Science and Technology, and Professor Bai Xiaochun from the School of Basic Medicine of Southern Medical University are the co-corresponding authors of the paper
.
Original link: https://doi.
org/10.
1038/s43587-021-00165-w Publisher: Eleven References 1.
Shane Anderson, A.
and RF Loeser, Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol, 2010.
24(1): p.
15-26.
2.
Chen, D.
, et al.
, Runx2 plays a central role in Osteoarthritis development.
J Orthop Translat, 2020.
23: p.
132-139.
3.
Latourte, A.
, et al.
, Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis.
Ann Rheum Dis, 2017.
76(4): p.
748-755.
4.
Wu, C.
, et al.
, Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis.
Nat Commun, 2015.
6: p.
7531.
Instructions for reprinting【Non-original article】The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
All legal rights, violators will be prosecuted
.
