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iNature osteoarthritis (OA) is an aging-related degenerative joint disease whose pathogenesis is still unclear
.
On February 10, 2022, Guozhi Xiao, Huiling Cao and Xiaochun Bai of Southern University of Science and Technology jointly published a research paper titled "Kindlin-2 preserves integrity of the articular cartilage to protectagainst osteoarthritis" in Nature Aging online.
High expression in chondrocytes and downregulation in degenerated cartilage from aging mice and OA patients
.
Deletion of Kindlin-2 in articular chondrocytes causes spontaneous osteoarthritis and exacerbates instability-induced osteoarthritis damage in adult mice
.
Kindlin-2 deficiency promotes mitochondrial oxidative stress, activates STAT3, and leads to Runx2-mediated chondrocyte catabolism
.
Pharmacological inhibition of STAT3 activation or gene knockout in chondrocytes reversed the abnormal accumulation of Runx2 and extracellular matrix-degrading enzymes, and limited OA exacerbation caused by kindlin-2 deficiency
.
Knockdown of Runx2 in chondrocytes reversed the structural changes and OA damage caused by kindlin-2 deletion without downregulating p-STAT3
.
Intra-articular injection of AAV5-kindlin-2 slows the progression of aging- and instability-induced knee osteoarthritis in mice
.
In conclusion, this study identifies a pathway consisting of kindlin-2, stat3 and runx2 in articular chondrocytes responsible for maintaining articular cartilage integrity and identifies a potential therapeutic target for OA
.
Degenerative arthritis is the most common degenerative joint disease and a leading cause of chronic disability in older adults worldwide
.
Causes of OA in humans include aging, joint overuse or damage, obesity, and genetics
.
Although OA is a total joint disease affecting articular cartilage, subchondral bone, and synovium, progressive loss of articular cartilage is a hallmark event of OA pathology
.
The molecular mechanisms underlying the occurrence, development, and progression of OA remain elusive
.
Therefore, there are currently no FDA-approved OA treatments or effective interventions to limit the progression of OA
.
Therefore, it is important to determine the control mechanisms of articular cartilage homeostasis under physiological conditions and to determine how they are altered in the OA state
.
Chondrocytes are the only cell type in articular cartilage and are surrounded by a collagen-rich extracellular matrix (ECM), the primary target of osteoarthritis cartilage degradation
.
Articular chondrocytes abnormally produce extracellular matrix-degrading proteases Mmp13 and Adamts4/5, which promote the degradation of extracellular matrix and the initiation and progression of osteoarthritis
.
It is well known that integrins are transmembrane receptors of the extracellular matrix, but studies on whether and how alterations in the extracellular matrix-integrin signaling pathway are involved in the initiation and progression of osteoarthritis remain controversial
.
Several studies using transgenic mouse models have shown that abnormal accumulation of Runx2 protein accelerates the onset and progression of osteoarthritis
.
Furthermore, activation of signal transducer and activator of transcription (STAT3) stimulates the initiation and progression of OA, whereas inactivation of STAT3 inhibits the initiation and progression of OA
.
However, key signaling molecules that maintain the integrity of articular cartilage remain poorly understood
.
Kindlin is a key focal adhesion protein that interacts with the cytoplasmic domain of β-integrin and activates the integrin to regulate cell-ECM adhesion, migration, and signaling
.
In mammalian cells, there are three Kindlin proteins, encoded by Fermt1, Fermt2, and Fermt3
.
They are: kindlin-1, kindlin-2 and kindlin-3
.
Human genetic diseases are associated with mutations in kindlin-1 and kindlin-3, but not kindlin-2
.
Kindlin-2 is essential for early embryonic development; inactivation of the gene encoding Kindlin-2 resulted in early embryonic death in mice at E7.
5
.
Previous studies on kindlin-2 have focused on its role in the regulation of tumor formation, progression and metastasis
.
Recently, its role in the regulation of organogenesis and homeostasis through integrin-independent mechanisms has received increasing attention
.
In addition, it has recently been demonstrated that kindlin-2 plays a critical role in regulating skeletal development and bone remodeling through distinct molecular mechanisms; however, it remains unclear whether kindlin-2 plays a role in articular cartilage homeostasis, and its function in articular chondrocytes Whether the changes in expression in osteoarthritis are involved in the occurrence and development of osteoarthritis
.
In this study, the study found that Kindlin-2 is highly expressed in healthy articular cartilage cells and downregulated in aged and OA cartilage
.
This study demonstrates that loss of inducible kindlin-2 in chondrocytes causes spontaneous osteoarthritis and exacerbates instability-induced osteoarthritis in adult mice
.
Kindlin-2 deficiency promotes chondrocyte catabolism through the STAT3-Runx2 pathway in articular chondrocytes, leading to OA
.
Intra-articular injection of AAV5-kindlin-2 attenuates OA damage induced by aging and instability in mice
.
Protective effect of intra-articular injection of AAV5-kindlin-2 on aging and DMM-induced OA in mice (Image courtesy of Nature Aging) In conclusion, this study identifies a pathway consisting of kindlin-2, stat3 and runx2 in articular chondrocytes , this pathway is responsible for maintaining the integrity of articular cartilage and has identified a potential therapeutic target for OA
.
Reference message: https://
.
On February 10, 2022, Guozhi Xiao, Huiling Cao and Xiaochun Bai of Southern University of Science and Technology jointly published a research paper titled "Kindlin-2 preserves integrity of the articular cartilage to protectagainst osteoarthritis" in Nature Aging online.
High expression in chondrocytes and downregulation in degenerated cartilage from aging mice and OA patients
.
Deletion of Kindlin-2 in articular chondrocytes causes spontaneous osteoarthritis and exacerbates instability-induced osteoarthritis damage in adult mice
.
Kindlin-2 deficiency promotes mitochondrial oxidative stress, activates STAT3, and leads to Runx2-mediated chondrocyte catabolism
.
Pharmacological inhibition of STAT3 activation or gene knockout in chondrocytes reversed the abnormal accumulation of Runx2 and extracellular matrix-degrading enzymes, and limited OA exacerbation caused by kindlin-2 deficiency
.
Knockdown of Runx2 in chondrocytes reversed the structural changes and OA damage caused by kindlin-2 deletion without downregulating p-STAT3
.
Intra-articular injection of AAV5-kindlin-2 slows the progression of aging- and instability-induced knee osteoarthritis in mice
.
In conclusion, this study identifies a pathway consisting of kindlin-2, stat3 and runx2 in articular chondrocytes responsible for maintaining articular cartilage integrity and identifies a potential therapeutic target for OA
.
Degenerative arthritis is the most common degenerative joint disease and a leading cause of chronic disability in older adults worldwide
.
Causes of OA in humans include aging, joint overuse or damage, obesity, and genetics
.
Although OA is a total joint disease affecting articular cartilage, subchondral bone, and synovium, progressive loss of articular cartilage is a hallmark event of OA pathology
.
The molecular mechanisms underlying the occurrence, development, and progression of OA remain elusive
.
Therefore, there are currently no FDA-approved OA treatments or effective interventions to limit the progression of OA
.
Therefore, it is important to determine the control mechanisms of articular cartilage homeostasis under physiological conditions and to determine how they are altered in the OA state
.
Chondrocytes are the only cell type in articular cartilage and are surrounded by a collagen-rich extracellular matrix (ECM), the primary target of osteoarthritis cartilage degradation
.
Articular chondrocytes abnormally produce extracellular matrix-degrading proteases Mmp13 and Adamts4/5, which promote the degradation of extracellular matrix and the initiation and progression of osteoarthritis
.
It is well known that integrins are transmembrane receptors of the extracellular matrix, but studies on whether and how alterations in the extracellular matrix-integrin signaling pathway are involved in the initiation and progression of osteoarthritis remain controversial
.
Several studies using transgenic mouse models have shown that abnormal accumulation of Runx2 protein accelerates the onset and progression of osteoarthritis
.
Furthermore, activation of signal transducer and activator of transcription (STAT3) stimulates the initiation and progression of OA, whereas inactivation of STAT3 inhibits the initiation and progression of OA
.
However, key signaling molecules that maintain the integrity of articular cartilage remain poorly understood
.
Kindlin is a key focal adhesion protein that interacts with the cytoplasmic domain of β-integrin and activates the integrin to regulate cell-ECM adhesion, migration, and signaling
.
In mammalian cells, there are three Kindlin proteins, encoded by Fermt1, Fermt2, and Fermt3
.
They are: kindlin-1, kindlin-2 and kindlin-3
.
Human genetic diseases are associated with mutations in kindlin-1 and kindlin-3, but not kindlin-2
.
Kindlin-2 is essential for early embryonic development; inactivation of the gene encoding Kindlin-2 resulted in early embryonic death in mice at E7.
5
.
Previous studies on kindlin-2 have focused on its role in the regulation of tumor formation, progression and metastasis
.
Recently, its role in the regulation of organogenesis and homeostasis through integrin-independent mechanisms has received increasing attention
.
In addition, it has recently been demonstrated that kindlin-2 plays a critical role in regulating skeletal development and bone remodeling through distinct molecular mechanisms; however, it remains unclear whether kindlin-2 plays a role in articular cartilage homeostasis, and its function in articular chondrocytes Whether the changes in expression in osteoarthritis are involved in the occurrence and development of osteoarthritis
.
In this study, the study found that Kindlin-2 is highly expressed in healthy articular cartilage cells and downregulated in aged and OA cartilage
.
This study demonstrates that loss of inducible kindlin-2 in chondrocytes causes spontaneous osteoarthritis and exacerbates instability-induced osteoarthritis in adult mice
.
Kindlin-2 deficiency promotes chondrocyte catabolism through the STAT3-Runx2 pathway in articular chondrocytes, leading to OA
.
Intra-articular injection of AAV5-kindlin-2 attenuates OA damage induced by aging and instability in mice
.
Protective effect of intra-articular injection of AAV5-kindlin-2 on aging and DMM-induced OA in mice (Image courtesy of Nature Aging) In conclusion, this study identifies a pathway consisting of kindlin-2, stat3 and runx2 in articular chondrocytes , this pathway is responsible for maintaining the integrity of articular cartilage and has identified a potential therapeutic target for OA
.
Reference message: https://
