Abstract
PEGPH20, a human recombinant hyaluronidase, has been proposed as a coadjutant to pancreatic cancer chemotherapy. In early trials, patients reported increased widespread muscle pain as the main adverse reaction to PEGPH20. To understand how PEGPH20 caused musculoskeletal pain, we systemically administered PEGPH20 to male mice and measured voluntary wheel activity and pain-related behaviors. These were paired with ex-vivo electrophysiology of primary sensory neurons, whole DRG realtime PCR, and immunohistochemistry of hindpaw muscle. PEGPH20 induced significantly lower wheel running, compared to vehicle treated animals, and decreased mechanical withdrawal thresholds 5 days after PEGPH20 injections. Chemo-sensory muscle afferents showed increased responses to noxious chemical stimulation of their receptive fields in the PEGPH20 treated group. This was correlated with upregulation of the NGF receptor TrkA, the transient receptor potential vanilloid type 1 (TRPV1) channel and ATP-sensitive channel P2X3 in the DRG. Immunohistochemistry of hindpaw muscles revealed damage to the muscle architecture and extensive infiltration of the tissue by cells of the myelomonocytic lineage 3 days after PEGPH20 injection. Peripheral macrophage ablation in macrophage Fas-induced apoptosis (MaFIA) mice, however, did not prevent the decreased voluntary activity and instead caused even lower levels of running. These results suggest that disruption of hyaluronic acid within the muscle extracellular matrix sensitizes chemo-nociceptive muscle afferents possibly leading to altered pain-like behaviors. Ablation experiments suggest macrophages are necessary for adequate recovery of voluntary activity after hyaluronic acid (HA) disruption. These data support a role for HA and macrophages in tissue integrity and muscle pain development in patients taking PEGPH20.
Significance Statement
Hyaluronidase co-administration has been suggested as a possible solution to improve the delivery of chemotherapeutic agents into difficult to access tissues. In clinical trials, patients receiving a systemic dose of hyaluronidase reported widespread pain as a side effect. Delivering hyaluronidase to mice, we found that they experienced decreased voluntary activity. We observed alterations in the response properties of metabo-nociceptive muscle afferents, accompanied by increased muscle infiltration of myeloid lineage cells including macrophages. Macrophage depletion at the time of hyaluronidase administration surprisingly exacerbated the decrease in voluntary activity. This suggests that increased hyaluronidase levels can affect muscle function and lead to immune responses, but also suggest these cells may be needed for muscle recovery to allow animals to perform activity-based tasks.
Footnotes
This research was performed while under a research contract with Halozyme Inc., manufacturers of the hyaluronidase product used (PEGPH20).
This work was partially funded by a research contract with Halozyme Inc. This work was also supported by a grant to MPJ from the NIH (R01NS113965).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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