Back pain is among the most common health problems and is frequently caused by damage to the discs between the vertebrae, known as intervertebral discs. These discs act as cushions, allowing for movement and absorbing mechanical forces.

As people age, these discs become stiff and wear out, which is a major risk factor for back pain. Cellular senescence, a process in which cells stop dividing and start releasing harmful cell products, contributes to this degeneration by damaging the surrounding cells. In aged or degenerated intervertebral discs, the number of senescent cells is significantly increased.

The protein PDGF is a growth factor involved in cell growth and division and is widely used in the clinical setting for tissue regeneration and repair. So far, it was unknown if PDGF could slow down cellular senescence in intervertebral discs.

To find out more, Zhang et al. collected two types of cells found in intervertebral discs – the nucleus pulposus cells and the annulus fibrosus cells – from tissue samples of healthy individuals and patients with disc hernias. They then treated these cells with PDGF and analyzed their gene activity. The experiments showed that PDGF slowed cellular senescence in both cell types. In both tissues, PDGF increased the expression of genes that promote the cell cycle and decreased the expression of genes related to senescence, including those involved in oxidative stress responses and mitochondrial dysfunction. Zhang et al. also noted some tissue-specific responses to PDGF treatment, with nucleus pulposus cells responding more by reducing the activity of genes involved in metabolic pathways, and annulus fibrosus cells by deactivating genes involved in responses to mechanical stimulation experienced during daily activities.

Zhang et al. further developed a ‘cellular senescence model’ by exposing healthy cells extracted from the nucleus pulposus and the annulus fibrosus to a single dose of senescence-inducing radiation in both cell types. Immediate treatment with PDGF reduced the expression of senescence-related genes.

In summary, the study indicates that PDGF can inhibit cell senescence in intervertebral discs. The next step will be to validate these findings in animal models and clinical trials to ensure safety and effectiveness. In the future, this could lead to new strategies for developing minimally invasive therapies to inhibit or halt the progression of degenerative disc disease within the ageing spine.

Low back pain (LBP), ranked as the first cause of years lived with disability, is a prevalent condition. Although the etiology of LBP is multifactorial, a major contributor of LBP is IVD degeneration, which is increasing exponentially due to a growing aged population worldwide (Feng et al., 2016). Current treatments, such as medicine, physical therapy, and surgical excision of the herniated tissues, only temporarily alleviate painful symptoms (Xin et al., 2022). In fact, patients often experience persistent LBP after surgery (Coronado et al., 2015). The fundamental cause of this is the inadequate knowledge of the underlying pathophysiology mechanisms leading to IVD degeneration. Therefore, it is crucial to understand the pathogenesis of IVD degeneration and develop novel therapeutic interventions to mitigate the degenerative processes.

The IVD consists of three compartments: the gelatinous nucleus pulposus (NP), fibrous annulus fibrosus (AF), and cartilaginous endplate (Sivan et al., 2014). NP and AF tissues play distinct yet complementary roles in maintaining the spinal function. The NP has a high content of proteoglycans and water, absorbing and distributing mechanical forces. In contrast, AF consists of multiple layers of concentric lamellae, which provide strength and stability to the disc and withstand compressive forces (Sivan et al., 2014; Pattappa et al., 2012). The NP plays a crucial role in the progression of IVD degeneration due to its susceptibility to significant structural and functional changes during aging and degeneration. Indeed, NP structural changes are easily detected through imaging techniques. Thus, because of its high water content, MRI has made the NP the most visible indicator of disc degeneration in clinical practice. In contrast, degenerated alterations in the AF are more closely linked to pain and disability. As a result, effective therapeutic strategies for IVD degeneration should aim to restore the functionality of the entire disc unit.

Cellular senescence, triggered by normal cells in response to various intrinsic and extrinsic stressors, is a fundamental mechanism underlying age-related chronic diseases. Senescent cells are featured by irreversible growth arrest and acquire a senescent-associated secretory phenotype (SASP) and the secretion of pro-inflammatory cytokines, chemokines, and tissue-damaging proteases (Ngo et al., 2017). Activation of P53/P21 and P16 pathways plays a critical role in regulating senescence (Reimann et al., 2024). In addition, the NF-κB pathway is a major pathway involved in the expression of pro-inflammatory mediators in senescent cells (Salminen et al., 2012). Factors within the SASP can act in an autocrine manner to reinforce the senescent state and induce senescence in neighboring cells via paracrine signaling (Kumari and Jat, 2021). This mechanism elucidates the accumulation of senescent cells with aging and its associated detrimental effects. In the IVD, it has been well established that the number of senescent cells increases with aging and IVD degeneration (Veroutis et al., 2021; Gruber et al., 2007; Gruber et al., 2009), as demonstrated by increased senescence-associated β-galactosidase (SA-β-Gal) positive cells and decreased cell proliferation. Growing research also demonstrates that targeting cellular senescence holds promise in alleviating the progression of IVD degeneration. Long-term systemic or local clearance of senescent cells by senolytic drugs mitigated age-related IVD degeneration in mice (Novais et al., 2021) and reduced the expression of pro-inflammatory cytokines and matrix proteases and restored IVD structure in an injury-induced IVD degeneration model in rats (Lim et al., 2022). Cherif et al. and Mannarino et al. demonstrated that in humans, senolytic drugs o-Vanillin (Mannarino et al., 2021), and RG-7112 (Cherif et al., 2020) attenuated NP cellular senescence, where a combination of these two senolytic drugs reduced the release of inflammatory factors and pain mediators in degenerated NP cells from low back pain patients (Mannarino et al., 2023).

PDGF is a major constituent of platelet-rich plasma (PRP), which is widely used in the clinical setting for tissue regeneration and repair. It can be made of a homodimer of A, B, C, and D polypeptide chains, or an AB heterodimer (Chen et al., 2013; Heldin and Lennartsson, 2013). Among these, PDGF-AB and -BB are the predominant forms in PRPs (Weibrich et al., 2002). Two types of PDGFR (PDGFRA and PDGFRB) were identified that differ in ligand-binding specificity. PDGFRA binds to all PDGF chains but D chain while PDGFRB only binds to B and D chains (Chen et al., 2013; Heldin and Lennartsson, 2013). Upon binding, the PDGF-PDGFR network induces a cascade of phosphorylation in pathways including cell proliferation, migration, and survival (Contreras et al., 2021). We previously demonstrated that recombinant human PDGF-BB (rhPDGF-BB) inhibited cell apoptosis while promoting cell proliferation and matrix production in human IVD cells (Presciutti et al., 2014). Furthermore, when delivered via hydrogel, rhPDGF-BB successfully inhibited IVD degeneration and restored IVD biomechanical function in a rabbit preclinical model of puncture-induced IVD degeneration (Paglia et al., 2016). In the current study, we hypothesize that PDGF-AB and -BB mitigated IVD degeneration by targeting cellular senescence. To test it, aged, degenerated human IVD cells were treated with rhPDGF-AB or -BB and transcriptome profiling was performed on treated NP and AF cells. We found similar but distinct responses to the treatment between NP and AF cells. In NP cells, PDGF-AB and -BB treatment upregulated the expression of PDGFRA and genes involved in cell cycle progression while downregulating the expression of genes related to ROS production, oxidative stress, and mitochondrial function. The alterations in these pathways indicated that the senescent phenotype was alleviated in human degenerated IVD cells treated with PDGF-AB/BB. Furthermore, in human senescent NP cells induced by irradiation, PDGFRA was significantly reduced, while PDGF-AB/BB treatment mitigated the progression of senescence through increased cell cycle progression and reduced SA-β-Gal staining and the expression of P21, P16, NF-κB, and IL6.

The current study has shown for the first time that PDGF-AB and -BB treatment not only alleviated the senescent phenotype, but also suppressed the progression of cellular senescence in the IVD. Specifically, in aged, degenerated human NP and AF cells, PDGF-AB/BB treatment suppressed the ROS accumulation, mitochondrial dysfunction, and the resultant oxidative stress, while stimulating cell cycle progression. In the NP, PDGFRA was among the top hub genes that showed strong interaction with other genes. Moreover, its expression was significantly reduced in irradiation-induced senescent cells. Importantly, immediate PDGF-BB treatment after irradiation promoted the expression of PDGFRA and mitigated senescence-associated phenotype in healthy IVD cells. This novel function of PDGF-BB/PDGFRA signaling is likely linked to their ability to inhibit NF-κB, P16, and P21 pathways in NP cells. In contrast, while PDGF treatment alleviated the senescent phenotype in AF cells, it also induced changes in pathways such as response to mechanical stimuli and neurogenesis, which were distinct from those in NP cells. This indicates that the treatment enhanced IVD functionality through different mechanisms within the two compartments. Senescence is a key contributor to the onset and the progression of IVD degeneration (Silwal et al., 2023). It can occur naturally with aging or can be triggered by growth factor deficiency, radiation, DNA damage, oxidative stress, and inflammatory stimuli (Wang et al., 2016; Huang et al., 2022). Senescent cells exit the cell cycle and cannot divide; their accumulation reduces the IVD’s ability to generate new cells to replace apoptotic or necrotic cells. It has been well established that an increased number of senescent cells was positively correlated with IVD aging and the severity of degeneration while negatively correlated with the percentage of proliferating cells in human NP and AF tissues (Gruber et al., 2009; Veroutis et al., 2021; Gruber et al., 2007). Since PDGF is a mitogenic growth factor and promotes cell proliferation in various cell types (Contreras et al., 2021; García-Olivas et al., 2007; Martin-Garrido et al., 2013), it is intriguing to explore whether PDGF-AB/BB could mitigate or prevent against cellular senescence in IVDs. We observed groups of upregulated genes regulating cell cycle progression and cell proliferation in PDGF-AB/BB-treated NP cells. AF cells also had an upregulation of chromosome segregation and mitotic nuclear division pathways, suggesting that these cells were actively proliferating. Cell cycle progression is controlled by cyclins, and the expression of cyclin D1 and B1, regulators of the G1/S and G2/M phase transition, respectively, was increased in degenerated NP cells after PDGF-AB/BB treatment. Transcriptomic analysis also revealed that increased cyclin D1 was among the top hub nodes, tightly regulated by PDGF-AB and BB. In addition, cell cycle analysis confirmed that PDGF-AB/BB induced the transition from G1 to S1 phase in senescent IVD cells. Our data suggested that PDGF treatment led to an increase in the proliferation of senescent IVD cells in the S phase likely through cyclin D1 and B1. These findings were in accordance with previous studies showing that PDGF-stimulated cell proliferation and cyclin D1 expression in rat mesangial cells (Hida et al., 2003), rat adventitial fibroblasts (Chen et al., 2024), and human vascular smooth muscle cells (Martin-Garrido et al., 2013).

The antisenescence of PDGF has been demonstrated in several studies. For example, PDGF-BB decreased SA-β-gal positive cells and the expression of P53 and P21 while enhancing proliferative potential in senescent human dermal fibroblasts (Bae et al., 2016) and mesenchymal stem cells (MSCs) derived from immune thrombocytopenia patients (Zhang et al., 2016). PDGF exerts its function by binding to its receptors, thereby triggering a cascade of intracellular signaling events, such as cell proliferation and survival. The PDGF-PDGFRA signaling is often suppressed in premature aged or senescent cells (Tan et al., 2018; Pan et al., 2019; Mori et al., 1993), suggesting that PDGF signaling dysfunction might be involved in senescence or aging. Notably, our transcriptome data has shown that both PDGF-AB and -BB induced the expression of PDGFRA in aged, degenerated NP cells. This autoregulatory loop caused IVD cells to become more sensitive to PDGF treatment and augmented the signaling cascades triggered by PDGF binding, including senescence-associated P21, P16, P53, and NF-κB pathways. In line with this thought, PPI analysis revealed that PDGFRA closely interacted with upregulated MDM2, a negative regulator of P53. NF-κB signaling is a major signaling pathway that is involved in inflamm-aging (Songkiatisak et al., 2022) and induces the onset of SASP (Salminen et al., 2012), such as IL6, IL8, and CXCL1. In our study, irradiation in NP cells led to decreased PDGFRA expression, which impaired the activity of PDGF/PDGFRA signaling. However, PDGF-BB treatment promoted the expression of PDGFRA and decreased the expression of P21, P16, and IL6 in senescent NP cells, likely by inhibiting NF-κB signaling. In fact, it has been shown that NF-kB signaling was elevated in mouse IVDs exposed to a single 20 Gy dose of irradiation in an ex vivo culture model (Liu et al., 2020). These findings support the idea that PDGF treatment could stimulate the expression of PDGFRA and mitigated the progression of senescent phenotype in healthy IVD cells. Interestingly, while mRNA level was increased in PDGF-treated NP cells, its protein level was decreased, highlighting the complexity in PDGF receptor dynamics. Upon binding with PDGF ligands, PDGFRA is known to undergo rapid internalization and degradation, a mechanism that prevents overstimulation of the signaling pathway (Rogers and Fantauzzo, 2020). The upregulated gene expression probably compensates for this degradation and supports continued activation of PDGFRA signaling activation, emphasizing its crucial role in response to the PDGF treatment. Further studies using preclinical animal models to validate the protectiveness of PDGF against the onset or progression of senescence in the IVD will offer more robust evidence.

Degenerated IVD cells experienced an imbalance between ROS accumulation and antioxidant capacity, leading to oxidative stress, which is involved in cellular senescence (Feng et al., 2017). Mitochondrion is the primary location of intracellular ROS production and its dysfunction in degenerated IVD cells causes electron leakage, resulting in the formation of superoxide radicals (Wang et al., 2022). PDGF-AB/BB treatment suppressed the activity of damaged mitochondria, leading to decreased ROS and oxidative stress in degenerated NP and AF cells, as indicated by GO BP analysis. Consistently, GSEA revealed the underrepresentation of oxidative phosphorylation in treated NP cells. The downregulation of genes related to mitochondria activity and oxidative phosphorylation may be indicative of a shift in metabolic pathways, leading cells to potentially prioritize alternative pathways such as glycolysis. Indeed, PDGF treatment upregulated groups of genes involved in response to decreased oxygen levels, suggesting that the treatment-activated cellular mechanisms involved in sensing and adapting to low oxygen conditions. In line with this idea, it has been demonstrated that hypoxia-inducible factor 1α is highly expressed in healthy NP cells to suppress oxidative phosphorylation and enhance glycolysis, allowing cells to adjust to a hypoxic microenvironment (Song et al., 2024; Silagi et al., 2021). Conversely, degenerated NP cells show an opposite metabolic pattern (Song et al., 2024; Silagi et al., 2021).

Besides the anti-senescence, NP and AF cells responded differently to PDGF-AB/BB treatment. AF cells were more responsive to the treatment with twice as many DEGs as NP cells. The difference in tissue architecture and cellular contents between NP and AF contributes to their specialized functions (Kudelko et al., 2021). The multiple layers of concentric lamellae in the AF enable it to withstand circumferential loads, while this highly organized structure was disrupted with aging and degeneration (Dittmar et al., 2016). In addition, damage to the AF has the potential to stimulate neovascularization and nerve ingrowth, provoking an inflammatory response and contributing to low back pain. PDGF-AB/BB treatment downregulated groups of genes related to neurogenesis and response to mechanical stimulus in AF cells, while downregulated genes in the NP were more associated with metabolic pathways, providing evidence that the treatment enhanced IVD functionality in different aspects between the two compartments.

Senescence as a central hallmark of aging can be induced by several factors (Silwal et al., 2023). One limitation of this study is that we did not examine the effects of PDGF-AB/BB treatment on senescence using other senescence models. In addition, our findings were obtained in vitro experiments, so caution is needed when interpreting our data. Our future work will focus on establishing an appropriate experimental animal model to study the functions of PDGF on cellular senescence.

In this study, we demonstrated a novel function of PDGF in human NP and AF cells. PDGF-AB/BB treatment alleviated oxidative stress and mitochondria dysfunction while stimulating cell cycle progression in degenerated IVD cells. In addition, the treatment mitigated the progression of senescence in healthy NP and AF cells following irradiation. These findings suggest that PDGF-AB/BB may serve as a promising potential candidate for IVD degeneration by targeting cellular senescence.

Sequencing data have been deposited in NCBI Sequence Read Archive database under the accession code PRJNA1150962. All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Changli Zhang

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. Atlanta VA Medical Center, Decatur, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1170-0374

2. Martha Elena Diaz-Hernandez

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. Atlanta VA Medical Center, Decatur, United States

   Contribution

   Conceptualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Takanori Fukunaga

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. Atlanta VA Medical Center, Decatur, United States

   Contribution

   Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Sreekala Shenoy

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. Atlanta VA Medical Center, Decatur, United States

   Contribution

   Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Sangwook Tim Yoon

   Emory Orthopaedics and Spine Center, Atlanta, United States

   Contribution

   Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1010-6952

6. Lisbet Haglund

   Department of Surgery, McGill University, Montreal, Canada

   Contribution

   Conceptualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1288-2149

7. Hicham Drissi

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. Atlanta VA Medical Center, Decatur, United States

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Visualization, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   hicham.drissi@emory.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3322-281X

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