P2Y receptors in bone

Bones are formed and remodeled by the coordinated actions of three key cell types. Osteoblasts, specialized connective tissue cells, deposit and then mineralize the collagenous bone matrix. Osteoclasts, which are derived from promonocytes, resorb mineralized matrix by excavating characteristic pits on bone surfaces. The third cell type, osteocytes, differentiates from osteoblasts that become trapped in bone matrix, forming a three‐dimensional network that is thought to detect deformations due to mechanical loading. This brief review summarizes what is known of the roles played by the G‐protein‐coupled P2Y receptors in modulating bone cell function. Current indications are that both osteoblasts and osteoclasts express P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y_12–14 receptors. The UTP/ADP‐sensitive P2Y₂ receptor, expression of which is highly upregulated in mature, bone‐forming osteoblasts, may play a significant role in limiting bone mineralization by inhibiting alkaline phosphatase expression. Extracellular adenosine triphosphate additionally exerts significant physicochemical (i.e., nonreceptor mediated) effects on mineralization via its hydrolysis product, pyrophosphate. The roles, if any, of P2Y receptors in osteocyte function are not well investigated, mainly because of the inaccessibility of these cells within bone. In osteoclasts, available evidence indicates that the P2Y₁, P2Y₆, and, possibly, P2Y₁₃ receptors could act to promote resorptive function. P2Y receptor‐mediated signaling has numerous and complex effects on bone cells; however, many of the key findings to date indicate that a large proportion of these actions may well be negative for bone. WIREs Membr Transp Signal 2012, 1:805–814. doi: 10.1002/wmts.67