ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation

Abou-Jaoude, Antoine; Courtes, Mathilde; Badique, L.; Mahmoud, D. Elhaj; Abboud, Clauda; Mlih, Mohamed; Justiniano, Hélène; Milbach, M; Lambert, M.; Lemle, Alexandre; Awan, Sara; Terrand, Jérôme; Niemeier, Andreas; Barbero, Andrea; Houard, Xavier; Boucher, Philippe; Matz, Rachel L.

doi:10.1016/j.joca.2022.07.001

Cited by 12 publications

(9 citation statements)

References 49 publications

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“…SFPQ is a key nuclear protein regulator (Splicing Factor Proline and Glutamine Rich), which is overexpressed in tumors and functions to promote tumor cells proliferation, chemical resistance, and invasion [8,9]. Runtassociated transcription factor 2 (RUNX2) is a master transcription factor for chondrocyte hypertrophy that plays an important role in osteoarthritis [10]. Researchers have demonstrated that chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…Runtassociated transcription factor 2 (RUNX2) is a master transcription factor for chondrocyte hypertrophy that plays an important role in osteoarthritis [10]. Researchers have demonstrated that chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction [10,11]. In addition, SFPQ could be competitively bound by various non-coding RNAs, thereby increasing the translation level of RUNX2 [12,13].…”

Section: Introductionmentioning

confidence: 99%

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P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

Nie

Deng

et al. 2023

J Orthop Surg Res

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Background The disruption of chondrocyte proliferation and differentiation is a critical event during the process of joint injury in osteoarthritis (OA). P-15 peptides could bind to integrin receptors on various precursor cells, promote cell adhesion, release growth factors, and promote the differentiation of osteoblast precursor cells. However, the role of P-15 in OA, particularly in chondrocyte proliferation, is not fully understood. Methods The activity of SFPQ and RUNX2 in the bone tissue of patients with osteoarthritis was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Interleukin-1β (IL-1β) inducer was performed to establish an in vitro model of OA. Cell proliferation was measured by CCK-8 assay. The expressions of COL2a1, ACAN, COMP, SOX9, and BMP2 related to cartilage differentiation were detected using qRT-PCR. In addition, the expression levels of SFPQ, AKT, p-AKT, and RUNX2 were detected using Western blotting. Results The results showed that the expression of SFPQ was significantly decreased and the expression of RUNX2 was significantly increased in osteoarthritis cartilage tissue. P-15 peptide reversed IL-1β-induced cell proliferation obstruction and alleviated chondrocyte damage. Furthermore, P-15 polypeptide increased the expression levels of cartilage differentiation genes COL2a1, ACAN, and BMP2, while decreasing the expression of COMP and SOX9 in an inverse dose-dependent manner. Then specific interfering RNA proved that P-15 maintains chondrocyte stability and is associated with the SFPQ gene. Finally, we confirmed that P-15 inhibited the Akt-RUNX2 pathway, which is regulated in the expression of SFPQ. Conclusions P-15 can mitigate chondrocyte damage and osteoarthritis progression by inhibiting cell death and modulating SFPQ-Akt-RUNX2 pathway, offering an opportunity to develop new strategies for the treatment of osteoarthritis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

Nie

Deng

et al. 2023

J Orthop Surg Res

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“…Of course, upregulation of SFPQ levels by P-15 leads to RUNX2 inhibition, and our data is exactly the same. Inconsistently, the transcription factor SOX9 activates collagen II expression and prevents the conversion of proliferating chondrocytes into hypertrophic chondrocytes by directly interacting with RUNX2 and repressing its activity [10,43]. Our data showed that P-15 reduces IL-1β-induced increase in SOX9, illustrating that in addition to inhibiting RUNX2 by controlling SFPQ access, P-15 might also activate RUNX2 by inhibiting SOX9 expression.…”

Section: Discussionmentioning

confidence: 63%

“…SFPQ is a key nuclear protein regulator (Splicing Factor Proline and Glutamine Rich), which is overexpressed in tumors and functions to promote tumor cells proliferation, chemical resistance, and invasion [8,9]. Runt-associated transcription factor 2 (RUNX2) is a master transcription factor for chondrocyte hypertrophy that plays an important role in osteoarthritis [10]. Researchers have demonstrated that chondrocyte hypertrophic differentiation, a key process in endochondral ossi cation, is also a feature of osteoarthritis leading to cartilage destruction [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…Runt-associated transcription factor 2 (RUNX2) is a master transcription factor for chondrocyte hypertrophy that plays an important role in osteoarthritis [10]. Researchers have demonstrated that chondrocyte hypertrophic differentiation, a key process in endochondral ossi cation, is also a feature of osteoarthritis leading to cartilage destruction [10,11]. In addition, SFPQ could be competitively bound by various non-coding RNAs, thereby increasing the translation level of RUNX2 [12,13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

Nie

Deng

et al. 2023

Preprint

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Background The disruption of chondrocyte proliferation and differentiation is a critical event during the process of joint injury in osteoarthritis (OA). P-15 peptides could bind to integrin receptors on various precursor cells, promote cell adhesion, release growth factors, and promote the differentiation of osteoblast precursor cells. However, the role it plays in OA, particularly in chondrocyte proliferation, is not fully understood. Methods The activity of SFPQ and RUNX2 in the bone tissue of patients with osteoarthritis was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Interleukin-1β (IL-1β) inducer was performed to establish an in vitro model of OA. Cell proliferation was measured by CCK-8 assay. The expressions of COL2a1, ACAN, COMP, SOX9, and BMP2 related to cartilage differentiation were detected using qRT-PCR. In addition, the expression levels of SFPQ, AKT, p-AKT, and RUNX2 were detected using Western blotting. Results The results showed that the expression of SFPQ was significantly decreased and the expression of RUNX2 was significantly increased in osteoarthritis cartilage tissue. P-15 peptide reversed IL-1β-induced cell proliferation obstruction and alleviated chondrocyte damage. Furthermore, P-15 polypeptide increased the expression levels of cartilage differentiation genes COL2a1, ACAN, and BMP2, while decreasing the expression of COMP and SOX9 in an inverse dose-dependent manner. Then specific interfering RNA proved that P-15 maintains chondrocyte stability and is associated with the SFPQ gene. Finally, we confirmed that P-15 inhibited the Akt-SUNX2 pathway, which is regulated in the expression of SFPQ. Conclusions P-15 can mitigate chondrocyte damage and osteoarthritis progression by inhibiting cell death and modulating SFPQ-Akt-SUNX2 pathway, offering an opportunity to develop new strategies for the treatment of osteoarthritis.

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New Insights on the Therapeutic Potential of Runt-Related Transcription Factor 2 for Osteoarthritis: Evidence from Mendelian Randomization

Xie,

Xu,

Yang

et al. 2024

Rheumatol Ther

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Introduction Research has highlighted the role of runt-related transcription factor 2 (Runx2) in the development of osteoarthritis (OA); however, its causal association remains unclear. This study aimed to explore whether Runx2 expression is causally associated with OA and assess its therapeutic potential for OA. Methods Genetic proxy instruments for Runx2 expression were obtained from gene expression quantitative trait locus (eQTLs) study of eQTLGen Consortium ( n = 31,684). Aggregated genome-wide association study (GWAS) data for OA (including all OA [177,517 cases and 649,173 controls], knee OA (KOA) [62,497 cases and 333,557 controls], and hip OA (HOA) [36,445 cases and 316,943 controls]) were extracted from the Genetics of Osteoarthritis Consortium. We integrated eQTLs data with OA GWAS data to estimate their causal association and to estimate the potential of Runx2 as a drug target in the treatment of OA using summary data-based Mendelian randomization (SMR) analysis. Furthermore, different OA GWAS data (including all OA [77,052 cases and 378,169 controls], KOA [24,955 cases and 378,169 controls], and HOA [15,704 cases and 378,169 controls]) derived from the GWAS Catalog database were used for replication study. Results SMR analysis showed that high expression levels of Runx2 were associated with an increased risk of all OA [odds ratio (OR) 1.044, 95% confidence interval (CI) 1.023–1.067; P = 5.03 × 10 −5 ], KOA (OR 1.040, 95% CI 1.006–1.075; P = 0.021), and HOA (OR 1.067, 95% CI 1.022–1.113; P = 0.003). This suggests that Runx2 inhibitors may have promising potential for the treatment of OA. Notably, the causal effects of Runx2 with all OA (OR 1.053, 95% CI 1.027–1.079; P = 3.95 × 10 −5 ) and KOA (OR 1.043, 95% CI 1.001–1.087; P = 0.045) were repeated in the replication study, but limited evidence supported the association of Runx2 expression levels with HOA (OR 1.045, 95% CI 0.993–1.101; P = 0.094). Conclusions Our analyses indicate a positive correlation between Runx2 expression and OA risk across all three phenotypes, suggesting the potential of Runx2 inhibitors in the treatment of OA and providing evidence from a genetic perspective. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-024-00682-1.

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ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation

Cited by 12 publications

References 49 publications

P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

P-15 promotes chondrocyte proliferation in osteoarthritis by regulating SFPQ to target the Akt-RUNX2 axis

New Insights on the Therapeutic Potential of Runt-Related Transcription Factor 2 for Osteoarthritis: Evidence from Mendelian Randomization

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