Aging-associated increase of GATA4 levels in articular cartilage is linked to impaired regenerative capacity of chondrocytes and osteoarthritis

Aging is an inevitable phenomenon resulting in limited functionality, loss of structural integrity, and inability to effectively resist injury and disease (Xiong et al., 2022). Osteoarthritis (OA), the world’s most common form of degenerative disease, has been closely associated with the advancement of age (Rahmati et al., 2017). Specifically, OA is estimated to affect 32.5 million Americans, with most cases occurring in adults over the age of 45 (Makarczyk et al., 2021). In fact, 1 in 3 people over the age of 65 are suffering from OA (Hawker and King, 2022). There are many contributors linked to the onset and progression of aging, such as organelle dysfunction and telomere shortening (Xiong et al., 2022), but the molecular mechanism underlying age-related OA has not been fully understood. Prior studies have demonstrated the role of DNA damage on chondrocyte aging due to oxidative stresses, resulting in an aged phenotype (Copp et al., 2022; Loeser et al., 2016). Aged cells can also undergo a state similar to permanent cell cycle arrest known as cellular senescence, which leads to a low-grade state of chronic inflammation and contributes to OA onset and progression in aged individuals (Loeser et al., 2016; Ji et al., 2022; Franceschi et al., 2000).

OA is now considered a whole joint disease, but cartilage degradation still represents the central feature (Makarczyk et al., 2021). The physiological role of articular cartilage is to support and protect the bones of diarthrodial joints through absorbing mechanical loads and facilitating frictionless movements. The extracellular matrix (ECM) of the cartilage is composed primarily of collagen type II and glycosaminoglycans (GAGs), and the constant breakdown and rebuilding of ECM components in the cartilage is common in healthy adults (Makarczyk et al., 2021; Makarczyk, 2023). Many growth factors contribute to the chondro-supportive environment in the knee joint. Particularly, transforming growth factor β (TGFβ) plays a key role in maintaining chondrocytes and replenishing ECM loss. However, during OA, TGFβ can induce catabolic processes in chondrocytes, resulting in matrix stiffening, osteophytes, and chondrocyte hypertrophy (Shen et al., 2014; Roman-Blas et al., 2007; van der Kraan, 2017). Furthermore, as we age, the regenerative response of chondrocytes begins to decline (Rahmati et al., 2017). The whole joint nature of OA and the limited regenerative capacity of chondrocytes have contributed to the difficulty in developing disease-modifying osteoarthritis drugs (DMOADs). To date, no DMOADs have reached FDA approval (Makarczyk et al., 2021).

Currently, OA-associated changes in chondrocytes have been widely examined, which have significantly enhanced our understanding of this disease and promoted the development of potential treatments. However, OA is a combined consequence of different physiological stressors, including aging, injuries, obesity, etc. Therefore, aged chondrocytes in healthy humans without OA do not necessarily exhibit all the features of OA chondrocytes. In this study, to understand key regulators that contribute to an ‘aged’ state in chondrocytes prior to OA onset, we first compared the transcriptome of young and old human chondrocytes isolated from healthy donors without joint diseases and employed unbiased analysis to define the key regulatory molecules that mediate chondrocyte aging. Assessment of the chondrocyte genome demonstrated the upregulation of several factors in aged chondrocytes, and transcription factor GATA-binding protein 4 (GATA4) specifically drew our attention since it is associated with DNA damage and cellular senescence (Copp et al., 2022; Kang et al., 2015). Mechanistically, upregulation of GATA4 was shown to increase nuclear factor κB (NFκB) pathway activation (Qiao et al., 2019; Jia et al., 2018). NFκB is thought to amplify and potentially propagate cellular senescence during the aging process through the senescence-associated secretory phenotype (SASP), which could contribute to a low-grade state of chronic inflammation (Rahman et al., 2022). Furthermore, the upregulation of GATA4 in OA chondrocytes was also reported (Kang et al., 2019; Schlett et al., 2023). We thus hypothesized that the increased GATA4 level contributes to chondrocyte aging and accelerated OA progression upon injuries. We first tested the hypothesis by increasing or suppressing GATA4 expression in healthy chondrocytes and examining their cartilage-forming capacity. When GATA4 was overexpressed, we found that there were alterations to the TGFβ signaling pathway and activation of the NFκB signaling pathway. We also assessed the role of GATA4 in vivo by injecting lentiviral vectors carrying control or mouse Gata4 genes into the knee joints of OA mice induced by surgically created destabilization of the medial meniscus (DMM). Lastly, a mechanistic study was conducted to explore how GATA4 impacts chondrocyte phenotypes and functions.

The causal relationship between aging and OA has been documented, and understanding the molecular mechanisms is essential for the development of treatment methods. In this study, we discovered the critical roles of aging-associated increases in GATA4 levels. Specifically, overexpressing GATA4 in young chondrocytes impaired their capacity to form normal hyaline cartilage, while suppressing GATA4 in old chondrocytes restored their chondrogenic potential. We also demonstrated that GATA4 functions partially by promoting the activation of SMAD1/5. Our in vivo work further confirmed that high Gata4 expression accelerated OA progression in mice. Lastly, we defined a small-molecule GATA4 inhibitor that can partially restore the capacity of old chondrocytes to create healthy cartilage, representing a potential DMOAD for further validation in the future.

Given the recognized challenges in harvesting healthy cartilage tissues from donors without arthritis, there are limited reports investigating chondrocyte aging per se. The current findings include proliferation and post-expansion chondrogenic capacity reduction with aging (Barbero et al., 2004), increased MMP13 production in response to catabolic stimuli (Forsyth et al., 2005), and altered response to TGFβ (van der Kraan, 2017). One of our recent studies again demonstrated that aged chondrocytes displayed a reduced proliferation potential compared to young cells. Additionally, cartilage tissues generated by old chondrocytes contained more senescent cells than those from young cells (Shen et al., 2021). However, to the best of our knowledge, there were no publications describing the transcriptomic comparisons between young and old chondrocytes, which would be informative in defining targets to stop or reverse chondrocyte aging.

Through transcriptomic analysis, we were able to assess the expression of different genes and genetic pathways that occur as chondrocytes age. Of note, hypoxia-inducible factor 1α (HIF1α) was the most differentially expressed gene predicted to regulate chondrocyte aging. The connection between HIF1α and aging has been previously reported (Yeo, 2019). Furthermore, additional studies have investigated HIF1α in association with OA and assessed its use as a therapeutic target (Hu et al., 2020; Zeng et al., 2022). Therefore, we decided to focus on GATA4, which was less studied in chondrocytes but highly associated with cellular senescence, an aging hallmark. However, our selection did not dampen the importance of HIF1α and other molecules listed in Figure 1D in chondrocyte aging. They can be further studied in the future using the same strategy employed in the current work.

The GATA family consists of several proteins (GATA1–6) with different variations of DNA-binding domains composed of zinc finger structures (Wang et al., 2022). Particularly, GATA4, 5, and 6 are involved in the development of the mesoderm and endoderm tissues (Romano and Miccio, 2020), in which GATA4 has been detected in the development of structures such as the heart (Dobrzycki et al., 2020; Ang et al., 2016), pancreas (Villamayor et al., 2020), lung, and liver (Tremblay et al., 2018; Molkentin, 2000). In addition, GATA4 and GATA6 are the only members that are associated with aging (Jiao et al., 2021). Particularly, GATA4 is unique in that it regulates tissues in a context-dependent manner and adopts a multifaceted role in the body, contributing to other age-related diseases such as atherosclerosis (Mahmoud et al., 2019) and heart failure (Katanasaka et al., 2016).

Furthermore, GATA4 might be associated with metabolic regulation. A study conducted by Patankar et al. investigated how GATA4 regulates obesity. Specifically, they used intestine-specific Gata4 knockout mice to study diet-induced obesity, showing that the knockout mice were resistant to the high-fat diet, and that glucagon-like peptide-1 (GLP-1) release was increased. These findings indicated a decreased risk for the development of insulin resistance in knockout mice (Patankar et al., 2011). This work was taken a step further in a subsequent publication, in which the same team investigated the dietary lipid-dependent and -independent effects on the development of steatosis and fibrosis in Gata4 knockout mice. The results from this work suggested that the knockdown of Gata4 increases GLP-1 release, in turn suppressing the development of hepatic steatosis and fibrosis, ultimately blocking hepatic de novo lipogenesis (Patankar et al., 2012). These studies are especially interesting with the rise of GLP-1-based therapy for the treatment of OA (Meurot et al., 2022; Yang et al., 2025). Thus, the coupling of GATA4-related metabolic dysfunction and OA should be further investigated.

In 2015, GATA4 was first introduced as a senescence regulator in a study conducted by Kang et al., 2015. This work demonstrated the role of GATA4 in human fibroblasts and determined that the inhibition of autophagy caused GATA4 accumulation following DNA damage. They examined the presence of GATA4 in the human brain and found that there was an increase of GATA4 in the prefrontal cortex of aged human samples (Kang et al., 2015). Further studies have shown that GATA4 regulates angiogenesis and inflammation in fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis, indicating that GATA4 is required for the inflammation induced by IL1β. This study also demonstrated that GATA4 binds to promoter regions on vascular endothelial growth factor (VEGF)-A and VEGFC to enhance transcription and regulate angiogenesis (Jia et al., 2018). In chondrocytes specifically, previous studies demonstrated that increased GATA4 levels are associated with chondrocyte senescence (Kang et al., 2019; Chung et al., 2023; Chung et al., 2020), an important change often observed in OA chondrocytes. Moreover, suppressing GATA4 with siRNA was shown to effectively abolish ionizing radiation-induced senescent phenotype in chondrocytes (Kang et al., 2019). Of note, all these studies relevant to chondrocytes were conducted in vitro. Herein, we, for the first time, demonstrate the role of GATA4 in regulating chondrocyte aging.

A theory of chondrocyte aging proposed by van der Kramm suggests that alterations to the TGFβ pathway induce chondrocyte hypertrophy and result in articular cartilage that is prone to OA development (van der Kraan, 2017). While investigating the function of GATA4 in chondrocytes, we assessed how its levels contribute to TGFβ alterations in chondrocytes and found that GATA4 levels negatively correlated with the anabolic potential of chondrocytes (Figures 2 and 4). Our study indicated that there was an observed decrease in chondrogenesis and an increase in hypertrophy-related genes following GATA4 overexpression (Figure 2G). To maintain healthy cartilage homeostasis, numerous pathways are involved. In particular, TGFβ is a crucial cytokine necessary for cartilage homeostasis during OA (Thielen et al., 2023; van der Kraan et al., 2012), and aged chondrocytes respond differently to TGFβ compared to their young counterparts (Baugé et al., 2014).

Mechanistically, in the TGFβ pathway, TGFβ binds to the heterotetrameric receptor complex, which can be grouped into three receptor types (type I, type II, and type III). When TGFβ binds to its corresponding receptor, the activin-receptor-like kinases (ALKs) are activated (van Caam et al., 2017). Typically, the anabolic binding of TGFβ to ALK4/5 results in the phosphorylation of SMAD2/3, protecting chondrocytes from hypertrophy (Thielen et al., 2023). However, there can also be catabolic effects associated with the expression of SMAD1/5, typically expressed when TGFβ binds to ALK1/2/3/6 (Thielen et al., 2023; van Caam et al., 2017). The phosphorylation of SMAD1/5 results in the promotion of ECM degrading proteins such as MMP13 (Vinuesa, 2021; Thielen et al., 2023). As mentioned previously, research has demonstrated that aged chondrocytes respond differently to TGFβ compared to young chondrocytes (Baugé et al., 2014; Wiegertjes et al., 2021). Chondrocyte aging has been linked to the increase of pSMAD1/5 signaling (Vinuesa, 2021). These previous studies and literature review inspired us to explore the potential association between GATA4 levels and the activation of SMAD1/5.

Our results found that GATA4 resulted in the phosphorylation of SMAD1/5 even without TGFβ stimulation, which however did not alter the phosphorylation of SMAD2/3. Although there are no current publications specifying the complex relationship of GATA4 and SMAD1/5 in chondrocytes, a prior study reported that GATA4 was regulated by SMAD1/5. Specifically, SMAD1/5 and GATA4 can bind together to promote IL6 expression in macrophages (Lee et al., 2010). In this study, it was shown that GATA4 was necessary for bone morphogenic protein 6 (BMP 6) mediated IL6 induction, in which there are multiple GATA binding domains on the IL6 promoter. This work further showed that GATA4 interacts with SMAD 2, 3, and 4 (Lee et al., 2010). Studies have suggested that BMP pathways and GATA4 work synergistically to regulate SMAD signaling (Güemes et al., 2014). This information indicates that the involvement of GATA4 in the TGFβ signaling pathway is complex, and further studies should be conducted to better assess this relationship.

Additionally, a common hallmark of chondrocyte aging is the alternation of ECM, including composition change (Rahmati et al., 2017) and stiffening (Iijima et al., 2023). The mechanical integrity of ECM can directly affect chondrocyte phenotype and proliferation and contribute to OA (Grogan and D’Lima, 2010). For example, aging induces increased lysyl oxidase-mediated collagen cross-linking and non-enzymatic advanced glycation end-products (AGEs) begin to accumulate, which stiffens the ECM collagen fibrils (Pokharna et al., 1995; Fan et al., 2022). On the other hand, aging is also associated with an increase in aggrecan fragmentation and a decrease in the GAG length and packing density (Lee et al., 2013), which leads to decreased osmotic pressure and compressive resistance. It was found that the indentation modulus of murine cartilage decreases with age, likely associated with the reduced aggrecan content, integrity, and osmotic pressure-endowed pre-tension within collagen fibrils (Fan et al., 2022). Meanwhile, earlier studies also indicate a softening effect of aging on cartilage tissue modulus (Kempson, 1982; Peters et al., 2018). To this day, there is still a paucity of knowledge on the mechanism by which aging impacts the ECM and its reciprocal interplay with resident cells.

Investigating ECM alterations in conjunction with cellular senescence and TGFβ signaling could provide further insights into cartilage aging. A recent study by Fu et al., 2024 associated matrix stiffening with the promotion of chondrocyte senescence. Furthermore, matrix stiffening has been associated with modulating the TGFβ signaling pathway (Vincent, 2013; Massagué, 2012; Allen et al., 2012). Future studies should investigate the potential of matrix stiffening and the effect of GATA4 on pericellular matrix proteins such as decorin (Chery et al., 2021; Li et al., 2020), biglycan, collagen VI and XV, as these proteins assist with the regulation of biochemical interactions and assist with the maintenance of the chondrocyte microenvironment (Chu et al., 2017). Herein, the TGFβ signaling pathway can further alter the extracellular microenvironment (Allen et al., 2012), which could promote cellular senescence and subsequently NFκB pathway activation. Further investigation of ECM alterations and aging could elucidate the molecular events governing these changes, providing key insights on the interplay between chondrocytes and their environment in the context of aging.

While the TGFβ pathway is closely associated with cartilage matrix remodeling, we also found increases in the levels of multiple proinflammatory cytokines after GATA4 overexpression. We investigated the NFκB pathway since it is also activated in aged tissues (Yao et al., 2023; Adler et al., 2007). During the aging process, NFκB is thought to amplify and potentially propagate cellular senescence through the SASP (Rahman et al., 2022). A study by Qiao et al., 2019 indicated that GATA4 regulates NFκB in dental pulp cells and fibroblasts (Jia et al., 2018). Specifically, using siRNAs, they determined that the knockdown of GATA4 decreased p65 production induced by lipopolysaccharide (LPS) (Qiao et al., 2019). Other studies have investigated the role of GATA4 in the synovium and the progression of the disease state of rheumatoid arthritis and OA. Jia et al., 2018 showed that the knockdown of GATA4 attenuated synovial inflammation and joint damage in a collagenase-induced arthritis mouse model. More recently, a study conducted by Chen et al., 2022 investigated the roles of GATA4 in FLSs and determined that GATA4 induced cellular senescence in FLSs in OA progression. Our study also discovered that the siRNA knockdown of GATA4 decreased the phosphorylation of p65 in aged chondrocytes (Figure 4). However, we also noticed that MMP13 expression levels decreased in both GATA4 overexpression and knockdown experiments. It should be noted that MMP13 is constitutively produced in human chondrocytes but is only activated under pathological conditions. Given that MMP13 is regulated by different transcriptional factors and cytokines, as well as RNAs (Vinuesa, 2021), its associations with GATA4 require further investigation in the future. Collectively, these findings further indicate that GATA4 might regulate aging partially through TGFβ and NFκB pathways.

Our current study has not fully explored why aging promotes GATA4 expression. The study from Kang et al., 2015 indicated that DNA damage contributed to GATA4 accumulation. It is known that DNA damage response (DDR) is regulated by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) signaling (Kang et al., 2015; Maréchal and Zou, 2013; Menolfi and Zha, 2020). The activation of these signaling pathways inhibits autophagy-related protein p62 (Wang et al., 2016). In addition, Copp et al., 2022 reported increased DNA damage in old chondrocytes. These studies implied that DNA damage may be a reason for GATA4 upregulation. Our preliminary data and prior work from Kang et al., 2015 support this possibility. Specifically, a DNA damage-inducing agent, doxorubicin, promoted the upregulation of GATA4 in chondrocytes (Figure 1—figure supplement 3). To further link DNA damage to GATA4 accumulation, a study by Chung et al. used Tributyltin (TBT), a well-known endocrine-disrupting chemical, to induce DNA damage in articular chondrocytes. After 24 hr of TBT treatment, there was a significant increase in GATA4 expression and expression of senescence markers (Chung et al., 2023). The study by Kang et al., 2015 demonstrated that the suppression of p62 following DNA damage leads to GATA4 accumulation due to the lack of autophagy. DNA damage is known to increase with age (Yousefzadeh et al., 2021). Therefore, we believe that DNA damage due to aging is a key driver of the upregulation of GATA4 in old chondrocytes.

In conclusion, we have determined that GATA4 is increased in aged chondrocytes compared to young in both humans and mice, which may be induced by increased DNA damage observed in aged cells. We also demonstrated that GATA4 overexpression impaired the quality and quantity of cartilage created by chondrocytes and accelerated OA progression in mice. Conversely, suppressing GATA4 with siRNA or small-molecule inhibitors partially restores the capacity of old chondrocytes to form cartilage. Additionally, our study found that GATA4 can activate SMAD1/5 and change chondrocyte response to TGFβ. Overall, our study indicated that GATA4 could be a contributor to OA onset and progression in aged individuals, which can also serve as a potential target to prevent aging-associated OA.

There are some limitations of this study that can be further addressed in future studies. First, this study has allowed us to examine the potential mechanisms of GATA4 in chondrocyte aging. Although we found that GATA4 was generally increased with aging, some young donors also exhibited increased levels of GATA4, which may be associated with increased DNA damage, as discussed above, or other stressors. Therefore, GATA4 should be used together in conjunction with other aging biomarkers, such as epigenetic clock (Sarkar et al., 2023) to precisely define chondrocyte aging. Future work should examine biological versus chronological aging and epigenetic clock-based assessments to explain the variabilities in GATA4 expression among donors. Second, the TGFβ signaling pathway is complex, and there are multiple studies that have associated it with GATA4. However, the relationship between GATA4 overexpression and SAMD1/5 activation should be further investigated to elucidate specific signaling mechanisms. Third, during our in vivo work, the intra-articular injection of GATA4 lentivirus was not chondrocyte-specific. Therefore, the injection also allowed for other cell types to overexpress GATA4. Future work should be conducted using transgenic mouse lines for cartilage-specific inducible overexpression or depletion of Gata4 to further investigate the role of GATA4 in chondrocytes. Furthermore, studies using GATA4 knockdown do not demonstrate a complete reversal of aging in chondrocytes, and additional in vivo assessment needs to be conducted to verify whether GATA4 could be a therapeutic target for chondrocyte aging. In particular, our in vitro study demonstrated the potential of using small-molecule GATA4 to enhance the quality of cartilage created by old chondrocytes. We can validate the findings in vivo, as well as develop other GATA4 inhibitors. Lastly, our work indicates that GATA4 has a role in chondrocyte aging, but that does not negate the other aging factors and pathways. Combining current findings and investigating the prevalence of GATA4 in association with other aging molecules will further contribute to our understanding of the role of GATA4 in aging and possible OA onset.

The raw and processed RNA-seq data were uploaded to Gene Expression Omnibus (GEO) with accession ID: GSE287861.

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Author details

1. Meagan J Makarczyk

   1. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States
   2. Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States

   Contribution

   Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Yiqian Zhang

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3444-8028

2. Yiqian Zhang

   1. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States
   2. Xiangya Hospital Central South University, Changsha, China

   Contribution

   Investigation, Methodology, Writing – original draft

   Contributed equally with

   Meagan J Makarczyk

   Competing interests

   No competing interests declared

3. Alyssa Aguglia

   Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

4. Olivia Bartholomew

   Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States

   Contribution

   Data curation, Visualization, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

5. Sophie Hines

   1. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States
   2. Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States

   Contribution

   Data curation

   Competing interests

   No competing interests declared

6. Kate Li

   Department of Biological Sciences, University of Pittsburgh Kenneth P. Dietrich School of Arts & Sciences, Pittsburgh, United States

   Contribution

   Data curation, Methodology, Visualization

   Competing interests

   No competing interests declared

7. Suyash Sinkar

   Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States

   Contribution

   Data curation

   Competing interests

   No competing interests declared

8. Silvia Liu

   1. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
   2. Organ Pathobiology and Therapeutics Institute, University of Pittsburgh School of Medicine, Pittsburgh, United States

   Contribution

   Formal analysis, Writing – original draft

   Competing interests

   No competing interests declared

9. Craig Duvall

   Department of Biomedical Engineering, Vanderbilt University, Nashville, United States

   Contribution

   Investigation, Writing – original draft

   Competing interests

   No competing interests declared

10. Hang Lin

    1. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States
    2. Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, United States
    3. Bethel Family Musculoskeletal Research Center (BMRC), University of Pittsburgh School of Medicine, Pittsburgh, United States

    Contribution

    Conceptualization, Formal analysis, Funding acquisition, Investigation, Writing – original draft, Writing – review and editing

    For correspondence

    hal46@pitt.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-0781-6630

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  citation for Reviewed Preprint v1 https://doi.org/10.7554/eLife.106224.1

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  citation for Reviewed Preprint v2 https://doi.org/10.7554/eLife.106224.2