Activation of the proton-sensing GPCR, GPR65 on fibroblast-like synoviocytes contributes to inflammatory joint pain DOI Creative Commons
Luke A. Pattison,

Rebecca H. Rickman,

Helen Hilton

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(51)

Опубликована: Дек. 11, 2024

Inflammation is associated with localized acidosis, however, attributing physiological and pathological roles to proton-sensitive receptors challenging due their diversity widespread expression. Here, agonists of the proton-sensing GPCR, GPR65, were systematically characterized. The synthetic agonist BTB09089 (BTB) recapitulated many proton-induced signaling events demonstrated selectivity for GPR65. BTB was used show that GPR65 activation on fibroblast-like synoviocytes (FLS), cells line synovial joints, results in secretion proinflammatory mediators capable recruiting immune sensitizing sensory neurons. Intra-articular injection resulted GPR65-dependent sensitization knee-innervating neurons nocifensive behaviors mice. Stimulation human FLS also triggered release inflammatory fluid samples from osteoarthritis patients shown activate These suggest a role mediating cell-cell interactions drive joint pain both mice humans.

Язык: Английский

The osteoarthritis associated sphingolipid sphingomyelin 34:1 causes inflammatory pain in mice DOI Creative Commons

Rebecca H. Rickman,

Luke A. Pattison,

Lanhui Qiu

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 19, 2024

Osteoarthritis (OA) is a condition affecting synovial joints that has multifactorial pathogenesis and where pain the main symptom driving clinical decision making. During OA, plethora of mediators are released by infiltrating immune cells resident cells, such fibroblast-like synoviocytes. Although roles certain OA-associated disease well-understood, there number molecules dysregulated in OA for which no role been identified. For example, dogs humans with dysregulation fluid lipidome occurs some findings have replicated studying plasma mouse model osteoarthritis. One upregulated lipid sphingomyelin N-palmitoyl-D-erythro-sphingosylphosphorylcholine (d18:1/16:0), also known as SM(d34:1), referred to here SM. This study investigated ability SM cause joint neuronal hyperexcitability mice. Overnight incubation sensory neurons either or structurally related ceramide produced decrease rheobase, i.e. hyperexcitability. By contrast, when injected into knee mice, SM, but not ceramide, evoked swelling, mechanical hyperalgesia decreased digging behaviour. Moreover, excitability retrograde traced, knee-innervating neurons, only those isolated from SM-injected mice exhibited The results generated demonstrate can contribute inflammatory pain, further work being necessary determine mechanism exerts its activity.

Язык: Английский

Процитировано

0
Activation of the proton-sensing GPCR, GPR65 on fibroblast-like synoviocytes contributes to inflammatory joint pain DOI Creative Commons
Luke A. Pattison,

Rebecca H. Rickman,

Helen Hilton

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(51)

Опубликована: Дек. 11, 2024

Inflammation is associated with localized acidosis, however, attributing physiological and pathological roles to proton-sensitive receptors challenging due their diversity widespread expression. Here, agonists of the proton-sensing GPCR, GPR65, were systematically characterized. The synthetic agonist BTB09089 (BTB) recapitulated many proton-induced signaling events demonstrated selectivity for GPR65. BTB was used show that GPR65 activation on fibroblast-like synoviocytes (FLS), cells line synovial joints, results in secretion proinflammatory mediators capable recruiting immune sensitizing sensory neurons. Intra-articular injection resulted GPR65-dependent sensitization knee-innervating neurons nocifensive behaviors mice. Stimulation human FLS also triggered release inflammatory fluid samples from osteoarthritis patients shown activate These suggest a role mediating cell-cell interactions drive joint pain both mice humans.

Язык: Английский

Процитировано

0