Leptin is a peptide hormone that is mainly synthesized in white adipose tissue and plays a regulatory role in energy metabolism and body weight. Beyond enhancing energy consumption in target cells, leptin can promote the production of pro-inflammatory cytokines, underlying the inflammatory and painful impacts of obesity. Both the leptin protein and the leptin receptor (LepR) have been detected in discs and are positively correlated with age and degeneration severity (11). While leptin can induce osteogenic differentiation in CEPs (17), the levels of leptin and its receptors increase with matrix metalloproteinase (MMP) and cytokine levels in the AF and NP of degenerative discs (12, 16, 39). Mechanistically, leptin can drive matrix catabolism via the Janus kinase-2 (JAK-2)/signal transducer and activator of transcription-3 (STAT-3) and mitogen-activated protein kinase (MAPK) pathways (13, 40). Additionally, leptin activates the ras homolog gene family member A (RhoA)/rho-associated coiled-coil containing protein kinase (ROCK) pathway and cytoskeletal remodeling in response to mechanical signals (15, 41). Although these findings suggest leptin has detrimental effects, whole-body leptin receptor knockout mice display delayed cellular proliferation and differentiation, elevated MMP-3 levels, and higher apoptosis rates, leading to IVDD (14, 18). Moreover, LepR has been identified as a lineage marker and fate modulator of notochord-derived cells at perinatal stages (42). Therefore, the potential fundamental role of leptin–LepR interactions in IVDD requires further exploration.

Adiponectin, a glycoprotein that is uniquely expressed by adipocytes, could maintain energy balance and suppress inflammation or apoptosis in various tissues by binding to adiponectin receptors (AdipoR1/2). However, the role of adiponectin and AdipoRs in IVDD is unclear. Previous studies showed that adiponectin expression in degenerative discs was decreased or absent while AdipoR1 and AdipoR2 expression increased or decreased with the Pfirrmann grade of degenerative discs (22, 43). However, plasma adiponectin levels were found to be increased in IVDD patients (44). Recently, administration of the AdipoR agonist AdipoRon was found to effectively reduce the levels of the pro-inflammatory factor tumor necrosis factor α (TNF-α) and mitigate disc degeneration (21). In future research, the exact role of adiponectin–AdipoR interactions in IVDD needs to be clarified.

PGRN, a secreted glycoprotein that can be cleaved into granulins by enzymes like elastase, exerts anti-inflammatory effects and plays protective roles by enhancing cell proliferation and through interacting with TNF receptors (TNFRs) or other receptors. Although higher PGRN levels are associated with higher degeneration severity in IVDD patients, current evidence suggests a protective role for PGRN in disc degeneration and aging (3, 45). Knockdown of PGRN in aged mice accelerates disc degeneration by promoting matrix catabolism and cellular dysfunction in AF and CEPs (29). Mechanistically, PGRN competitively binds to TNFR-1, thereby inhibiting the expression of the pro-inflammatory factor interleukin-17 (IL-17) and inflammatory and catabolic pathways (30, 45). Moreover, PGRN promotes anabolism and the production of the anti-inflammatory factor IL-10 via binding to TNFR-2 (28, 30). Additionally, PGRN and its derivatives, like atsttrin, inhibit epoxide synthase-2, IL-6, IL-17, and MMP-13 production, thereby inhibiting IVDD progression (29, 30).

Resistin is a cysteine-rich polypeptide that is secreted by white adipocytes and is involved in insulin resistance. In agreement with the devastating effect of diabetes on IVDs, recent research indicates resistin’s involvement in IVDD for its pro-inflammatory properties (46). By targeting Toll-like receptor-4 (TLR-4), resistin activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling to increase the expression of the macrophage inflammatory protein chemokine C-C motif ligand 4 (CCL4), thereby fostering macrophage infiltration into discs (19). In addition, resistin triggers inflammatory cascades through the activation of the MAPK and NF-κB pathways, which increases the NLR family pyrin domain containing 3 protein (NLRP3) inflammasomes and the expression levels of IL-1β, IL-6, IL-8, and MMPs in discs (20, 47).

Chemerin is an obesity-associated adipokine and is involved in various processes including inflammation by interacting with chemokine-like receptor 1 (CMKLR1). The expression levels of chemerin and CMKLR1 are increased in degenerative NP tissues, especially those of obese individuals (31). Furthermore, the administration of chemerin results in inflammation and tissue degeneration, while CMKLR1 knockdown could slow the progression of needle-induced disc degeneration in rats (31). Furthermore, chemerin exerts pro-senescent and pro-inflammatory effects on NP cells through binding to TLR-4, a well-known receptor activating the NF-κB signaling cascade (31, 48).

Visfatin, identified as the extracellular form of nicotinamide-phosphate ribosyl transferase (NAMPT), has been known to mediate insulin resistance and inflammation via binding to the insulin receptor or the innate immune receptor TLR-4. Visfatin could induce IL-6 expression and disc degeneration by activating the MAPK pathway, which participates in the inflammatory response (26). In addition, pharmacological inhibition or knockdown of visfatin resulted in the maintenance of metabolism balance by enhancing autophagy in the presence of IL-1β (24). Interestingly, a recent study showed that NAMPT was delivered in small extracellular vesicles derived from adipocytes (Adipo-sMV) and mediated the protective impact of Adipo-sMV through increased nicotinamide adenine dinucleotide (NAD) and NAD-dependent deacetylase sirtuin-1 (SIRT1) activity in senescent NP and CEP cells (23). Considering the lack of a secretion signal sequence, visfatin/NAMPT may play a multifaceted role dependent on its location: serving as the rate‐limiting enzyme for NAD⁺ biosynthesis in the cytosol or binding receptors on the cellular surface after leakage into the extracellular space.

Omentin-1, an anti-inflammatory adipokine, exhibits anti-inflammatory and antioxidant properties. Its expression level is inversely correlated with the progression of various diseases, including diabetes, obesity, and osteoarthritis (49, 50). Recent studies showed that omentin-1 could protect NP cells from ongoing senescence, inflammation, apoptosis, or matrix metabolism imbalance in the presence of IL-1β through activating SIRT1 or the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, also known as Akt) signaling pathway (32, 49). Therefore, it is valuable to further investigate its in vivo therapeutic potential in IVDD treatment.

OPG is a typical osteokine recognized as the regulator of bone mass and the receptor activator of NF-κB (RANK)/RANK ligand (RANKL) pathway, while it exists in various extraosseous tissues including discs. Various studies have shown a significant correlation between the levels of OPG in serum or disc samples and degeneration severity (62, 63, 81, 82). Further, OPG gene polymorphisms and increased OPG expression levels may contribute to IVDD development (81). OPG and RANK/RANKL expression could be upregulated with increased catabolism in AF, NP, or CEP cells exposed to acidic microenvironments or the inflammatory factor IL-1β (63, 64). However, OPG knockout results in osteoclast-mediated cartilage erosion, leading to disorganized alignment of CEPs, enhanced bone formation or neovascularization, and elevated inflammatory factors in mice (65–67). Thus, the multifaceted role of OPG in disc homeostasis highlights that further research is needed to elucidate its mechanism in IVD biology.

Sclerostin and DKK-1 are a pair of physical activity-related osteokines that competitively bind to the Wnt coreceptors lipoprotein receptor-related proteins (LRPs) and mediate the crosstalk between bone and other organs. Recently, sclerostin and DKK-1 have been shown to be involved in spinal pathological conditions, including spinal ligament ossification, spondylarthritis, and disc calcification (66, 67, 83). A recent study illustrated the compensatory increase in DKK-1 levels and the suppression of the Wnt/β-catenin pathway in sclerostin-depleted murine discs, and the administration of antibodies against sclerostin or DKK-1 exhibited beneficial effects on proteoglycan content, disc hydration, and height (84). Considering the complex role of Wnt signaling in disc development and degeneration, it is needed to clarify the exact roles and determinants of these Wnt inhibitors in IVDD (85).

PTHrP, first discovered in malignancy-associated hypercalcemia, has been recognized as an osteokine acting in a paracrine manner on bone and other tissues through binding to the PTH-1 receptor (PTH-1R). PTHrP is involved in intervertebral disc maturation and calcification, delays cellular mineralization and hypertrophy in Col IX knockout mice, and inhibits progressive kyphoscoliosis in fibroblast growth factor receptor-3 (FGFR-3) knockout mice (83–85). By enhancing Hedgehog, transforming growth factor beta (TGF-β), Wnt/β-catenin, mammalian target of rapamycin (mTOR), and MAPK/protein kinase A (PKA) signaling, PTH-1R activation by PTH administration plays a protective role in NP cell activity and disc homeostasis (69–72, 74). Considering the elevated PTH-1R expression in NP cells, the role of PTHrP–PTH-1R interactions in IVDD ought to be elucidated in future research (73, 86).

BMPs are osteokines participating in the formation and maintenance of bone and various non-bone tissues, including cartilage (51, 87). Various studies confirmed the presence of BMPs, including BMP-2, 4, 7, and 14 (also known as growth differentiation factor -5 [GDF-5]), with their receptors (BMPR-I/II) in the IVD (88–92). Mechanistically, BMP-2 and BMP-7 activate various signaling pathways, including the Smad/Puma and PI3K/Akt signaling pathways, to inhibit NP cell apoptosis or senescence (75, 76). Additionally, GDF-5 deficiency in mice results in notable matrix abnormalities and disc degeneration, which could be substantially restored by treatment with recombinant human GDF5 (93, 94). Due to their anti-inflammatory and pro-regenerative effects, recombinant human BMPs are used for bone grafting in vertebral fusion surgery as well as disc tissue engineering (95, 96).

Osteonectin, also known as secreted protein acidic and rich in cysteine (SPARC), is one of the most abundantly expressed non-collagenous proteins in mineralized tissues as well as non-mineralized tissues and orchestrates inflammation and tissue remodeling through binding to TLR-4, BMPRs, integrin receptors, and various growth factors. SPARC expression in human disc cells decreases with age and disc degeneration (97). Moreover, SPARC-deficient mice exhibit spontaneous disc degeneration and lower back pain, evidenced by an age-dependent increase in neuron markers like calcitonin gene-related peptide and Neuropeptide-Y within the discs and peripheral nerves (78, 98, 99). Additionally, these mice demonstrate a diminished lumbar neutral zone, increased spinal stiffness, and reduced spinal mobility (100). SPARC knockout results in elevated levels of inflammatory mediators and vascular endothelial growth factor, which can be mitigated by interventions like exercise and treatment with TAK-242 (a TLR-4 antagonist) or reparixin (an inhibitor of CXC chemokine receptors [CXCR1/2]) (80, 101–103). Therefore, SPARC is a promising target for preventing IVDD in modulating cell–matrix interactions and governing neural, immune, and inflammatory pathways (79, 104, 105).

Periostin is a bone turnover-related osteokine that is highly expressed in collagen-rich tissue—including periosteum—and mediates tissue remodeling through binding to integrin receptors and proteoglycans. In human and rat discs, periostin levels gradually decrease from the outer AF to the central NP and increase with degeneration development (106–108). Mechanistically, periostin promotes NP cell apoptosis via the Wnt/β-catenin signaling pathway and cellular senescence via the NF-κB pathway, contributing to the development of IVDD (109, 110). Considering its role as a matricellular protein, further investigation is needed to elucidate whether periostin participates in the regulation of disc cell–matrix interactions (111).

Lipocalin-2 (LCN-2), a glycoprotein secreted by osteoblasts and adipocytes, functions as a pro-inflammatory factor in obesity-related metabolic disorders, despite our limited understanding of the potential LCN-2 receptors (112, 113). A recent study suggested a correlation between LCN-2 and the expression of inflammation-related genes in human discs (114). Moreover, upregulated expression of LCN-2 has been validated to increase MMP-9 activity in AF cells (115). Considering that LCN-2 could function as a biomechanical and inflammatory sensor in bone–cartilage crosstalk, its specific role in IVDD needs to be elucidated (9).

Fibroblast growth factor-23 (FGF-23) is the first identified osteokine that can bind to the tyrosine kinase FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism (116). However, direct evidence linking FGF-23 to IVDD is currently lacking. Klotho, a crucial cofactor for FGF-23 in the activation of FGFRs, mitigates inflammation in NP cells and counteracts extracellular matrix degradation in IVDD (117, 118). Accordingly, the role of FGF-23 in IVD homeostasis, potentially analogous to that of Klotho, presents an intriguing avenue for further investigation.

Irisin is a well-characterized myokine derived from fibronectin type III domain-containing protein 5 (FNDC5). It mediates the health benefits of exercise by binding with integrins. Exercise elevated irisin levels in plasma and NP tissue and FNDC5/irisin knockout abolished the protective effects of exercise against IVDD in a murine model (114). By activating autophagy or large tumor suppressor kinase (LATS)/yes-associated protein (YAP)/connective tissue growth factor (CTGF, also known as CCN2) signaling, irisin can help maintain cellular activity and matrix metabolism balance and inhibit inflammatory effects, thereby decelerating the progression of IVDD (115, 117).

Myostatin (also known as GDF8) functions as a negative regulator of skeletal muscle growth. It binds to activin receptors (ACVRs) and can be expressed in back muscles after IVD injury (118, 137). However, the role of myostatin in IVDD is incompletely understood. Myostatin plays an inhibitory role in cartilage formation and chondrocyte proliferation, and its serum levels exhibit a positive correlation with the severity of conditions such as osteoarthritis and rheumatoid arthritis (121, 138). Additionally, ACVR1 silencing reversed lipopolysaccharide-induced inflammation and matrix degradation in NP cells, implying the potential unfavorable impacts of ACVR1 activation by myostatin upon discs (120). However, earlier studies indicated the fundamental role of myostatin in disc homeostasis. Myostatin deficiency in mice resulted in increased muscle weight, accompanied by endplates ossification at the L4–L5 level and a notable reduction in proteoglycan content in the endplates and inner AF (122, 139). Therefore, more comprehensive research is needed to elucidate the potential mechanism underlying the multi-faceted role of myostatin–ACVRs interactions in IVDD.

Apelin, identified as the endogenous ligand for the G-protein coupled receptor APJ, plays a regulatory role across diverse tissues including skeletal muscle and the cardiovascular system. Apelin and its receptor APJ are downregulated in degenerative NP tissue (123, 124). Moreover, administration of apelin results in suppressed matrix degradation, apoptosis, and inflammation in the presence of IL-1β and increased matrix anabolism in the presence of the oxidative stress inducer H₂O₂ (123, 124). Mechanistically, apelin enhances the PI3K/Akt pathway and transcription factor EB (TFEB)-mediated autophagy flux in NP cells (123, 124). Considering the significant role of apelin in exercise-induced benefits, exploring whether and how apelin participates in muscle–disc crosstalk is valuable (140).

Follistatin-like-1(FSTL-1) is a kind of myokine and cardiokine modulating immune responses, cell proliferation, and differentiation through binding to TLR-4, Wnt receptors, and various growth factors. FSTL-1 has an adverse effect on disc homeostasis, accompanied by increased concentrations in the serum of IVDD patients, discs of rats with IVDD, and the cerebrospinal fluid of dogs with IVDD (125, 141). Mechanistically, FSTL-1 promotes NP cell inflammation by activating the MAPK, Smads, or NF-κB signaling pathway (125, 141). Interestingly, the knockout of FSTL-1 during embryonic development leads to a decrease in vertebral cartilage and matrix anabolism, indicating its fundamental role in early IVD formation (142). Moreover, FSTL-1 may play diverse roles in disc development and maturation, given that it could mediate the differentiation of pre-cartilaginous stem cells into NP-like cells (143).

As a typical cardiokine, ANP binds to natriuretic peptide receptors (NPRs) to induce diuretic, natriuretic, and vasodilating effects and regulate the renin–angiotensin–aldosterone system (144). NPR mutations can result in impaired cartilage development, potentially leading to secondary degenerative changes and suboptimal joint development (145, 146). Recent studies indicated that ANP inhibited oxidative damage and cell death in endplates by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway (128). Additionally, given the presence and adverse effects of the local tissue renin–angiotensin system (tRAS) in discs, whether ANP has a protective impact via suppressing the tRAS in IVDD is an interesting avenue for future research (147–149).

Ghrelin is a circulating brain–gut peptide hormone that promotes growth hormone secretion via binding to the growth hormone secretagogue receptor (GHSR) and participates in the regulation of insulin resistance, obesity, and inflammation. Ghrelin was found present in the NP tissue, and ghrelin administration demonstrated a protective effect in a rabbit IVDD model (132). Mechanistically, ghrelin suppresses IL-1β-induced catabolism and inflammatory cytokine production by inhibiting the NF-κB pathway, while promoting anabolism via Akt signaling (132).

Glucagon-like peptide-1(GLP-1), a peptide hormone secreted by intestinal L-cells, has broad pharmacological potential for managing type 2 diabetes mellitus and metabolic syndrome-related disorders by binding to its receptor -GLP-1R. GLP-1R activation leads to the inhibition of inflammation and apoptosis through downstream pathways including the PKA, PKC, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways (156, 157). Notably, GLP-1R activation by liraglutide (a long-acting GLP-1 analog) has been shown to protect NP cells against hyperglycemia-induced apoptosis via the PI3K/Akt signaling pathway (134, 135). Administration of another GLP-1R agonist, exenatide, in discs promotes matrix synthesis and mitigates oxidative stress-induced matrix catabolism via inhibiting the activation of MAPK and activator protein-1 (AP-1) activity (133). Considering the therapeutic potential of GLP-1 activation, there is a need to further elucidate the role of endogenous GLP-1 in IVDD.

Amylin, also known as islet amyloid polypeptide (IAPP), is a peptide that is predominantly secreted by pancreatic islet β-cells and participates in the development of diabetes through receptor activity-modifying proteins (RAMPs) or the calcitonin receptor (CTR) to inhibit insulin and glucagon secretion. During IVDD progression, amylin and its receptors are downregulated in the NP and AF cells, while amylin aggregates accumulate in NP tissues (129–131). Amylin overexpression in NP cells can maintain matrix metabolism balance and control the autophagy–apoptosis crosstalk by the PI3K/Akt/mTOR and MAPK signaling pathways (130). Meanwhile, these protective effects could be augmented by neutralizing IL-1β/IL-1 receptor antagonist (IL-1Ra) signaling induced by amylin aggregation (129). Furthermore, the amylin analog pramlintide showed the ability to relieve matrix metabolism impairment and enhance cell survival via a mitochondrial-dependent apoptotic pathway in NP cells (158). Additionally, amylin activates Akt/mTOR signaling to protect AF cells from death through the death receptor Fas/FasL and the mitochondrial-dependent apoptotic pathway (131).

Hepatokines, such as angiopoietin-like proteins (ANGPTLs) and fetuin-A (also known as α2-HS-glycoprotein), are hormone-like proteins secreted by hepatocytes (159). ANGPTLs act as modulators of lipid metabolism, angiogenesis, and inflammation via binding to integrin receptors and immunoglobulin-like receptors. However, their roles in regulating disc homeostasis are poorly understood. Recent research illustrated the correlation between the upregulation of ANGPTL4/8 and the severity of disc degeneration (160, 161). Mechanistically, ANGPTL4/8 appears to promote matrix degradation and the production of inflammatory cytokines like TNF-α through the activation of the NF-κB signaling pathway (161, 162). Fetuin-A functions as an indirect inhibitor of ectopic mineralization and inflammation. Recent studies demonstrated that intra-articular injection of fetuin-A derivatives leads to improved osteoarthritis scores and mobility in a rat osteoarthritis model (163). Thus, it is worthwhile to explore the role of fetuin-A in IVDD.