Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

Abstract

Osteoarthritis (OA) is characterized by cartilage destruction and chondrocytes have a central role in this process. With age and inflammation chondrocytes have reduced capacity to synthesize and maintain ATP, a molecule important for cartilage homeostasis. Here we show that concentrations of ATP and adenosine, its metabolite, fall after treatment of mouse chondrocytes and rat tibia explants with IL-1β, an inflammatory mediator thought to participate in OA pathogenesis. Mice lacking A2A adenosine receptor (A2AR) or ecto-5′nucleotidase (an enzyme that converts extracellular AMP to adenosine) develop spontaneous OA and chondrocytes lacking A2AR develop an ‘OA phenotype' with increased expression of Mmp13 and Col10a1. Adenosine replacement by intra-articular injection of liposomal suspensions containing adenosine prevents development of OA in rats. These results support the hypothesis that maintaining extracellular adenosine levels is an important homeostatic mechanism, loss of which contributes to the development of OA; targeting adenosine A2A receptors might treat or prevent OA.

How to influence the mesenchymal stem cells fate? Emerging role of ectoenzymes metabolizing nucleotides

“…Despite the increased level of NTPDases expression in chondrogenically induced MSCs, the activity of these enzymes toward ATP remains quite low. This is in agreement with the latest study on NTPD1 knock-out mice that did not suffer from decreased ATP hydrolysis and Ado production (Corciulo et al, 2017). Supported by literature data, we hypothesize that structure-function relationships in chondrogenic lineage dictate the direction of nucleotides metabolism.…”

“…Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, and the application of both agents enhanced it by 380%. Considering the regulatory role of Ado in the cartilage, the A2A receptor agonists have been recently claimed to be a promising target for the treatment of OA since mice lacking the A2A receptors spontaneously develop the disease (Corciulo et al, ).…”

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

“…the pathogenesis of OA by inducing the chondrocyte anabolic and catabolic imbalance, including the downregulation of Collagen II and Aggrecan, as well as the upregulation of ADAMTS-5 and MMP-13 [45][46][47]. Therefore, we treated chondrocytes with IL-1b to simulate the OA microenvironment in vitro, similar to other studies [10,48]. When chondrocytes were exposed to IL-1b, we observed the same SGK1 expression pattern as detected in OA cartilage.…”

“…Among these pro‐inflammatory cytokines, increased IL‐1β levels have consistently been observed in the cartilage tissue, synovial fluid and the blood of patients with OA , and it plays a critical role in the pathogenesis of OA by inducing the chondrocyte anabolic and catabolic imbalance, including the downregulation of Collagen II and Aggrecan, as well as the upregulation of ADAMTS‐5 and MMP‐13 . Therefore, we treated chondrocytes with IL‐1β to simulate the OA microenvironment in vitro , similar to other studies . When chondrocytes were exposed to IL‐1β, we observed the same SGK1 expression pattern as detected in OA cartilage.…”

Functionally graded multilayer scaffolds for in vivo osteochondral tissue engineering

“…Adenosine signaling via the P1 receptor family of G protein-coupled receptors plays a key role in bone formation and homeostasis [52,53]. Recently, emerging studies have shown that adenosine signaling also plays a key role in regulating chondrocyte function and cartilage homeostasis [54,55]. Taken together, the single-unit scaffold may have provided a combination of chemical and structural cues that support osteochondral tissue formation.…”