Effects of an adenosine kinase inhibitor and an adenosine deaminase inhibitor on accumulation of extracellular adenosine by equine articular chondrocytes

Abstract

Articular chondrocytes accumulated extracellular ADO when exposed to LPS or ITU. Chondrocytes exposed to ITU accumulated ADO in a time-dependent manner. Unstimulated chondrocytes did not accumulate ADO. Similarly, EHNA alone did not produce detectable ADO concentrations; however, addition of EHNA and ITU resulted in a synergistic effect on accumulation of ADO. Lipopolysaccharide-induced NO production was more effectively suppressed by exposure to ITU than to EHNA CONCLUSIONS AND CLINICAL RELEVANCE: Equine articular chondrocytes release ADO in response to the proinflammatory stimulus of bacterial LPS. Inhibition of the metabolism of ADO increases accumulation of extracellular ADO. Autocrine release of ADO from chondrocytes may play a role in the cellular response to tissue damage in arthritic conditions, and pharmacologic modulation of these pathways in joints of arthritic horses could be a potential method of therapy.

Pulsed electromagnetic fields reduce knee osteoarthritic lesion progression in the aged Dunkin Hartley guinea pig

“…Modulation of extracellular adenosine concentration or modulation of adenosine receptor activity is suggested to represent a natural mechanism of controlling inflammation and a novel pathway for intervention in arthritic diseases [37,44,46]. Adenosine limits inflammatory response through receptor-mediated regulation of different cell types.…”

Regulation of bone and cartilage by adenosine signaling

“…Chondrocytes communicate with each other via diffusible signals rather than direct cell-to-cell contact, and are capable of adenosine release in response to various physiological stimuli [88]. Healthy cartilage requires tight regulation of extracellular adenosine levels; if the levels become depleted, increases in glycosaminoglycan (GAG) release, production of matrix metalloproteinases (MMP-3, MMP-13), prostaglandin E2 and nitric oxide (NO) can lead to increased inflammation and may trigger cell death [89].…”

“…In fact, ADA levels correlate with disease severity in RA [93]. Treatment of chondrocytes with iodotubercidin (ITU), an adenosine kinase inhibitor, leads to higher levels of extracellular adenosine and reduced levels of PGE2 and NO release [88]. The use of ITU also reduces GAG release, which is a marker of proteoglycan degradation and cartilage damage.…”

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

“…The presence of nucleoside transporters in articular cartilage has not been established. A recent study suggests that bacterial lipopolysaccharides (LPS) stimulate adenosine release from equine articular cartilage chondrocytes (27). However, the possibility remains that the adenosine originated from LPS-induced ATP release and cell surface dephosphorylation.…”

“…In cultures of equine articular chondrocytes, adenosine (1-100 M) and specific A 2A agonists reduced nitric oxide (NO) production in response to LPS (165,169). Erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride, an inhibitor of adenosine deaminase (adenosine 3 inosine), also reduced LPS-induced NO synthesis (27).…”