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GEOFFREY BURNSTOCK AN. R. ACAD. NAC. FARM.

In a recent study, deletion of the P2X7 receptor revealed its
regulatory roles in bone formation and resorption. It reduces bone
resorption by decreasing osteoclast survival (18). The multiple
purinoceptors on bone and cartilage also represent potential targets
for the development of novel therapeutics to inhibit bone resorption
in diseases such as rheumatoid arthritis, osteoporosis, tumour-
induced osteolysis and peridontis.

Nucleotide metabolism is tightly controlled in the cartilage
extracellar matrix. Apart from modulating purinoceptor activation,
ectoenzymes can regulate the levels of extracellular phosphate and
pyrophosphate, the components involved in crystal deposition.
Mechanical stimulation, which is critical for the maintenance of
healthy articular cartilage, can influence the rate of nucleotide
release and metabolism. The repair of foetal, but not adult, articular
cartilage involves the intercellular transfer of ATP, increase of [Ca2+]i
and expression of cfos in cartilage.

Tendinosis is a disorder characterised by acute or chronic pain
and degenerative change in the matrix. Mechanical loading induces
ATP release from tendon cells and stimulates expression of
interleukin IL-1ß, Cox2 and metalloproteinases as a negative
feedback mechanism to limit activation of the injurious pathway.
Attenuation of the feedback mechanism may result in the progression
of tendinosis.

Ultrasound is often used to accelerate fracture healing. It has
been shown recently that osteoblasts respond to ultrasound
stimulation by increasing ATP release, which appears to mediate
stimulation of osteoblast gene expression and cell proliferation.

A role for purinergic signalling in rheumatic diseases has been
considered for some time. Quinacrine (Atabrine), a drug that binds
strongly to ATP, has been used for the treatment of rheumatoid
arthritis patients for many years, one of its mechanisms of action
being to decrease levels of prostaglandin E2 and Cox-2, which are
known to be produced following occupation of P2Y receptors by
ATP. The articular fluid removed from arthritic joints contains high
levels of ATP. Purinergic regulation of bradykinin-induced plasma
extravasation and adjuvant-induced arthritis has been reported. ATP
and UTP activate calcium-mobilizing P2Y2 or P2Y4 receptors and act

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