Paracrine and endocrine functions of osteocytes.

Osteocytes are dendritic-shaped cells embedded in the bone matrix and are terminally differentiated from osteoblasts. Inaccessibility due to their location has hindered the understanding of the molecular functions of osteocytes. However, scientific advances in the past few decades have revealed that osteocytes play critical roles in bone and mineral metabolism through their paracrine and endocrine functions. Sclerostin produced by osteocytes regulates bone formation and resorption by inhibiting Wnt/β-catenin signaling in osteoblast-lineage cells. Receptor activator of nuclear factor κ B ligand (RANKL) derived from osteocytes is essential for osteoclastogenesis and osteoclast activation during postnatal life. Osteocytes also secrete fibroblast growth factor 23 (FGF23), an endocrine FGF that regulates phosphate metabolism mainly by increasing phosphate excretion and decreasing 1, 25-dihydroxyvitamin D production in the kidneys. The regulation of FGF23 production in osteocytes is complex and multifactorial, involving many local and systemic regulators. Antibodies against sclerostin, RANKL, and FGF23 have emerged as new strategies for the treatment of metabolic bone diseases. Improved undrstanding of the paracrine and endocrine functions of osteocytes will provide insight into future therapeutic options.