Abstract
As an important hormone that regulates the balance of calcium and phosphorus, parathyroid hormone (PTH) has also been found to have an important function in intervertebral disc degeneration (IVDD). Our aim was to investigate the mechanism by which PTH alleviates IVDD. In this study, the PTH 1 receptor was found to be highly expressed in severely degenerated human nucleus pulposus (NP) cells. We found in the mouse model of IVDD that supplementation with exogenous PTH alleviated the narrowing of the intervertebral space and the degradation of the extracellular matrix (ECM) caused by tail suspension (TS). In addition, inflammation, oxidative stress, and apoptosis levels were significantly increased in the intervertebral disc tissues of TS-induced mice, and the activity of NP cells was decreased. TS also led to the downregulation of Sonic hedgehog (SHH) signalling pathway-related signal molecules in NP cells such as SHH, Smoothened, and GLI1. However, supplementation with exogenous PTH can reverse these changes. In vitro, PTH also promotes the activity of NP cells and the secretion of ECM. However, the antagonist of the SHH signalling pathway can inhibit the therapeutic effect of PTH on NP cells. In addition, a cAMP-response element-binding protein, as an important transcription factor, was found to mediate the promotion of PTH on the SHH signalling pathway. Our results revealed that PTH can alleviate IVDD by inhibiting inflammation, oxidative stress, and apoptosis and improving the activity of NP cells via activating the SHH signalling pathway.
Highlights
Degenerative disc disease is one of the most common musculoskeletal disorders and a leading cause of disability [1, 2]
Human nucleus pulposus (NP) tissues were classified into Grade 2 (G2), G3, G4, and G5 groups according to the Pfirrmann grade (G1 was not included due to only mild degeneration)
Our study found that the expressions of SOD1, SOD2, and CAT in the parathyroid hormone (PTH)-treated mouse intervertebral disc NP tissues were significantly increased compared with the model group, and their expressions increased with increased PTH concentration, indicating that PTH can improve the oxidative stress state of intervertebral discs
Summary
Degenerative disc disease is one of the most common musculoskeletal disorders and a leading cause of disability [1, 2]. The NP contains the extracellular matrix (ECM), including collagen II, proteoglycan, and NP cells [3]. The biological mechanism of intervertebral disc degeneration (IVDD) is unclear. Current studies have shown that these factors including ECM degradation, inflammation, oxidative stress, and decreased activity of NP cells are important in inducing IVDD [4–6]. The hedgehog signalling pathway is composed of receptors and ligands named hedgehog proteins, which are secreted proteins, including Sonic hedgehog (SHH), Indian hedgehog (IHH), and Desert hedgehog (DHH) [7, 8]. Both SHH and IHH produce secreted proteins that bind to the transmembrane protein PATCH&ED (PTCH), thereby activating the hedgehog signalling pathway [7].
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