Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

Abstract

In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca 2+ , inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca 2+ release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.

Enhancement of Lumbar Fusion and Alleviation of Adjacent Segment Disc Degeneration by Intermittent PTH(1-34) in Ovariectomized Rats

“…However, these changes were effectively attenuated by PTH(1-34) treatment. Consistent with a previous study, Madiraju and colleagues (28) reported that PTH can stimulate type II collagen and proteoglycan synthesis by acting via MAPK and PKA signaling pathways to retard intervertebral disc (IVD) degeneration. Thus, PTH(1-34) treatment retards ASDD partly by regulating molecular metabolism.…”

“…Parathyroid hormone (PTH) has been shown to increase vertebral bone mass in patients with postmenopausal osteoporosis, (15) promote fracture healing, (16) and improve spinal fusion. (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) Moreover, Madiraju and colleagues (28) reported that PTH stimulates matrix synthesis and suppresses markers of calcification potential in degenerated disc cells via MAPK and PKA signaling pathways. Furthermore, Ishikawa and colleagues (29) reported that PTH stimulated the synthesis of cellular and extracellular proteins by growth plate chondrocytes.…”

Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity

“…The matrix of the intervertebral disc is mainly composed of Aggrecan, collagen and elastin, and oestrogen and parathyroid hormone (PTH) have an important role in promoting their metabolism1516. In addition, oestrogen receptors α and β were found in both the NP and the AF, and experiments confirmed that oestrogen can directly improve the proliferative activity of cells in the NP and annulus fibrosus and reverse their apoptosis171819.…”

Preconditioning of mesenchymal stromal cells toward nucleus pulposus-like cells by microcryogels-based 3D cell culture and syringe-based pressure loading system

“…After pressure loading with 0.2 MPa or 0.8 MPa for three days, expressions of NP related gene SOX9, COL II , and ACAN were all upregulated. COL I and COL X were reported to highly express when NP tissue underwent degeneration . After preconditioning, both of the two genes were downregulated in our system.…”

“…COL I and COL X were reported to highly express when NP tissue underwent degeneration. 49 After preconditioning, both of the two genes were downregulated in our system. Subsequent injection and histological staining proved the successful implantation of MSCs-laden PMs in vivo, where chondrogenic commitment to NP-like cells was maintained.…”