Sphingosine-1-phosphate (S1P), the product of phosphorylation of sphingosine by sphingosine kinase, is an important lipid signalling molecule for which biological functions continue to be defined. A new study by researchers working at the National Institute of Allergy and Infectious Diseases (NIAID) has now demonstrated a key role for S1P in bone remodelling. This process involves two major types of bone cells: osteoclasts, which break down bone and osteoblasts, which make new bone. Bone resorption and bone formation are normally finely balanced but, in conditions such as osteoporosis and rheumatoid arthritis, osteoclast activity exceeds osteoblast activity leading to a net decrease in bone density.
Immature osteoclasts circulate within the blood and migrate to the surface of the bones, where they mature and start to degrade the bone matrix. These immature cells were shown to express functional S1P1 receptors and migrate along an S1P gradient in vitro. Specialised imaging techniques were used to show that the S1P1 agonist, SEW2871, also stimulated motility in vivo. In a mouse model of postmenopausal osteoporosis, treatment of ovariectomized mice with the S1P1 agonist, FTY720, reduced osteoporosis by reducing the number of mature osteoclasts attached to the bone surface. FTY720 also acts as an immunosuppressant by preventing egress of lymphocytes from the lymph nodes, and is undergoing phase III clinical trials for the treatment of relapsing-remitting multiple sclerosis.
Most current treatments for osteoporosis target mature osteoclasts, and regulating migration of immature osteoclasts to the bone surface may offer a new approach to treating the disease.
The study, published in the journal Nature, was available online on February 8th.