TY - JOUR
T1 - Metastatic Infiltration of Nervous Tissue and Periosteal Nerve Sprouting in Multiple Myeloma-Induced Bone Pain in Mice and Human
AU - Diaz-DelCastillo, Marta
AU - Palasca, Oana
AU - Nemler, Tim T.
AU - Thygesen, Didde M.
AU - Chávez-Saldaña, Norma A.
AU - Vázquez-Mora, Juan A.
AU - Ponce Gomez, Lizeth Y.
AU - Jensen, Lars Juhl
AU - Evans, Holly
AU - Andrews, Rebecca E.
AU - Mandal, Aritri
AU - Neves, David
AU - Mehlen, Patrick
AU - Caruso, James P.
AU - Dougherty, Patrick M.
AU - Price, Theodore J.
AU - Chantry, Andrew
AU - Lawson, Michelle A.
AU - Andersen, Thomas L.
AU - Jimenez-Andrade, Juan M.
AU - Heegaard, Anne Marie
N1 - Publisher Copyright:
Copyright © 2023 the authors.
PY - 2023/7/19
Y1 - 2023/7/19
N2 - Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP1) and growth associated protein 43 (GAP431) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP.
AB - Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP1) and growth associated protein 43 (GAP431) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP.
KW - cancer-pain
KW - hematology
KW - multiple myeloma
KW - myeloma
KW - pain
KW - sprouting
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U2 - 10.1523/JNEUROSCI.0404-23.2023
DO - 10.1523/JNEUROSCI.0404-23.2023
M3 - Article
C2 - 37286351
AN - SCOPUS:85165518935
SN - 0270-6474
VL - 43
SP - 5414
EP - 5430
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 29
ER -