Parathyroid hormone‐related peptide activates and modulates TRPV1 channel in human DRG neurons

Abstract

Parathyroid hormone-related peptide (PTHrP) is associated with advanced tumor growth and metastasis, especially in breast, prostate and myeloma cancers that metastasize to bones, resulting in debilitating chronic pain conditions. Our recent studies revealed that the receptor for PTHrP, PTH1R, is expressed in mouse DRG sensory neurons, and its activation leads to flow-activation and modulation of TRPV1 channel function, resulting in peripheral heat and mechanical hypersensitivity. In order to verify the translatability of our findings in rodents to humans, we explored whether this signalling axis operates in primary human DRG sensory neurons. Analysis of gene expression data from recently reported RNA deep sequencing experiments performed on mouse and human DRGs reveals that PTH1R is expressed in DRG and tibial nerve. Furthermore, exposure of cultured human DRG neurons to PTHrP leads to slow-sustained activation of TRPV1 and modulation of capsaicin-induced channel activation. Both activation and modulation of TRPV1 by PTHrP were dependent on PKC activity. Our findings suggest that functional PTHrP/PTH1R-TRPV1 signalling exists in human DRG neurons, which could contribute to local nociceptor excitation in the vicinity of metastatic bone tumor microenvironment.

Mechanisms and treatment of bone pain in multiple myeloma

“…This signalling axis requires further research, particularly exploring the inhibition of PTHrP and its potentially analgesic effect on multiple myeloma-induced bone pain. Furthermore, the experiment confirmed the presence of this axis in humans after the initial identification in mice, this result, therefore, gives researchers confidence that this can be explored in in-vivo models with therapeutic intent, with the suggestion that findings in mice will translate into human models effectively [16].…”

“…The confirmation of this pathway in humans was achieved by immunohistochemistry and calcium ion imaging on human dorsal root ganglions. This pathway, therefore, presents a potential therapeutic target to modulate the pain experienced from the breakdown of bone in an environment of pH below six [16].…”

Teriparatide relieves ovariectomy-induced hyperalgesia in rats, suggesting the involvement of functional regulation in primary sensory neurons by PTH-mediated signaling

“…Consistently, NHERF2 was not detected in ROS 17/2.8 cells, a rat osteoblastic line 38 . Recent work reported that activation of PTHrP/PTH1R mediated signaling in cultured human DRGs was suggested to be involved in peripheral heat and mechanical hypersensitivity 39 , suggesting opposite neural function of PTHrP and PTH although they share the same receptor; PTH1R. Their binding preferences to different conformations of PTH1R may cause distinct neuronal function as proposed in osteoblast lineage cells 40 .…”

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

“…For example, E-selectin is considered as an effective adjuvant therapeutic drug to disrupt the interaction between cancer cells and bone marrow, especially in the cancers metastasizing to the bone, stressing the importance of regulating bone marrow microenvironment in inhibiting bone metastases (Muz et al, 2021). Additionally, PTH-related peptide is highly related to bone metastasis and leads to chronic pain in patients (Shepherd et al, 2018). While it is also worth noticing that metastasized cancer cells produce PTH-related peptide to induce RANKL, thus accelerating bone resorption, in turn, bone resorption further stimulates the release of tumor growth factors, resulting in promotion of tumor growth in bone and bone metastasis (Takayanagi, 2020).…”