Disruption of hyaluronic acid in skeletal muscle induces decreased voluntary activity via chemosensitive muscle afferent sensitization in male mice

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 real-time PCR, and immunohistochemistry of hindpaw muscle. PEGPH20 induced significantly lower wheel running, compared with vehicle-treated animals, and decreased mechanical withdrawal thresholds 5 d after PEGPH20 injections. Chemo-sensory muscle afferents showed increased responses to noxious chemical stimulation of their receptive fields (RFs) 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 d 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 (HA) within the muscle extracellular matrix (ECM) 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 HA disruption. These data support a role for HA and macrophages in tissue integrity and muscle pain development in patients taking PEGPH20.

Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming

“…1D, 3E, and our previous work 5 ). Since withdrawal thresholds are one of the most utilized behavioral readouts, it may be prudent to consider multiple behavioral assays when performing experiments depleting macrophages 5,21,38,88,89 . This confound is not a major concern for adolescent/adult behaviors, however, because the animal’s immune system had recovered before the second injury (Fig.…”

“…Preparation. This preparation has recently been described in detail 88 . In this study, pups were treated with either AP or vehicle as described above and were subjected to a P7 incision followed by a P35-P42 incision.…”

Development of an Antibody Delivery Method for Cancer Treatment by Combining Ultrasound with Therapeutic Antibody-Modified Nanobubbles Using Fc-Binding Polypeptide

“…Combination therapy with agents such as hyaluronidase may mitigate tumor barriers. However, the combination therapy has not been used widely for clinical applications since multiple organ damages were caused by these agents [ 15 , 16 ]. Therefore, the development of noninvasive approaches for antibody delivery is essential for use in clinical settings.…”

“…However, systemic injections of these agents pose the risk of unexpected side effects due to non-specific action—this is a major problem to be solved [ 15 , 16 ]. Recently, drug-delivery systems combined with micro/nanobubbles and ultrasound have been used to enhance the localization and accumulation of drugs and gene therapeutics in target tissues without damaging normal tissues [ 17 , 18 , 19 , 20 ].…”

A novel potential strategy for the treatment of inflammatory and neuropathic pain

“…Multiple research groups have proposed hyaluronan and its breakdown as a potential mechanism that mediates the development of pain in a variety of animal models. 1,2,4,18 The effects of hyaluronan on nociception, whether it is high or low molecular weight, seem to be the consequence of combined activation of the cluster of differentiation 44 (CD44) receptor, 8 toll-like receptor 4 (TLR4), 2 and receptor for hyaluronanmediated motility (RHAMM). 5 The data points toward HMWH as an antinociceptive signal, whereas low-molecular-weight hyaluronan (LMWH) is pronociceptive and induces local mechanical hyperalgesia.…”