Purinergic signalling in the musculoskeletal system

Abstract

It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y 1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

Purinergic signalling-evoked intracellular Ca2+ concentration changes in the regulation of chondrogenesis and skeletal muscle formation

“…P2X 4 , P2X 5 , P2X 7 , P2Y 1 and P2Y 4 receptors have also been demonstrated on multinucleated mouse myoblasts, in addition to P2X 6 receptors that have been described in developing rat skeletal muscle [50]. Metabotropic P2Y receptors could also be detected on developing C2C12 mouse myotubes and on embryonic skeletal muscle; furthermore, P2Y 1 , P2Y 2 and P2Y 4 receptors were also shown to be only temporarily expressed in the embryonic developmental stage and down-regulated in postnatal life [36].…”

“…Although ATP reversibly activated RyRs, AMP and adenosine were much weaker agonists [56]. Ca 2+ influx into C2C12 cells via P2X receptors contributes to the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2); ATP, ADP, 2MeSADP, UTP and UDP induced a transient increase in the level of p42 and p44 phosphorylation [50,57]. This process was fully Ca 2+ dependent.…”

“…GTP has also been shown to play a role in the early phases of skeletal muscle differentiation [55]. Whilst purinergic receptors clearly play significant roles during the development of skeletal muscle, differentiated muscle fibres barely express them; nonetheless, they reappear after denervation [50].…”

Lack of effect of adenosine on the function of rodent osteoblasts and osteoclasts in vitro

“…0 indicates that there were no viable cells present suggesting toxicity at concentrations of ≥10 μM 2-chloroadenosine. Data are means ± SEM for six replicate determinations (n = [3][4][5] present, the A 3 receptor knockout has not been investigated for specific changes in the bone; however, no overt changes in phenotype have been noted [52]. Adenosine receptors display widespread expression and are involved in many biological processes including coronary vasodilation [53], VEGF production, angiogenesis [54,55] and nerve transmission [56].…”

“…The roles played by P2X and P2Y receptors in regulating the function of bone cells have received considerable attention in recent years [4]. Osteoblasts, the bone-forming cells, express multiple P2 receptors [5,6], in a differentiationdependent manner [7,8], and respond to extracellular nucleotides with a prompt increase in intracellular calcium [7][8][9][10].…”