Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

Abstract

We propose that the extracellular matrix signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by the pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A and Src, but not protein kinase C, significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the extracellular matrix that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.

The stiffness of a crosslinked hyaluronan hydrogel affects its chondro‐induction activity on hADSCs

“…We have previously found that the chondrogenic effect of HA on ADSCs is mainly through CD44, one of the HA receptors . Moreover, signalling via CD44 has been shown to increase responses to mechanical stimulation through protein kinase A (PKA) and Src . On the basis of previous studies and the results presented here, we suggest that the difference in matrix stiffness of 3 D HA hydrogels may affect the chondrogenesis of ADSCs via CD44 signalling.…”

Anti–nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery–induced pain

“…For example, currently the most commonly used endpoint in skeletal pain behaviors is skin hypersensitivity as assessed by von Frey (mechanical testing) or the Hargreaves method (thermal) [2; 20; 51; 67]. While it may be peripheral and/or central sensitization [15; 21; 29; 50; 60; 64] that is driving this skeletal injury induced skin hypersensitivity, from the perspective of a patient with skeletal pain due to osteoarthritis or TKA/THA, evoked skin hyperalgesia is rarely the major pain complaint [18; 55; 62]. Rather the major complaint of patients with orthopedic surgery pain is the spontaneous pain that arises upon use of the bone/joint that interferes with their quality of life, functional status, and ability to participate in the needed physical therapy and rehabilitation [10].…”

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System

“…Direct interactions between HA and the transient receptor potential cation channel subfamily V member 1 (TrpV1; also known as the capsaicin receptor) expressed by dorsal root ganglion neurons decreased receptor activation and sensitization, leading to reduced responses to capsaicin and heat [ 70 ]. Loss of HA through hyaluronidase administration to the footpad of rats increased pain sensitivity in a CD44 dependent manner [ 71 ], suggesting that HA can also influence neuronal activity at sensory neuron endings. HA has also been found to modulate the activities of CNS neurons.…”