Paracrine and endocrine functions of osteocytes

Abstract

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.

Keywords: bone mass; fibroblast growth factor 23; osteocytes; phosphate metabolism; sclerostin.

Fig. 1.

Paracrine and endocrine functions of osteocytes. Osteocytes produce paracrine factors, sclerostin and receptor activator of NF-κB ligand (RANKL). Sclerostin produced by osteocytes inhibits Wnt/β-catenin signaling in osteoblasts (OB) in a paracrine manner, leading to the suppression of their proliferation and differentiation, the up-regulation of RANKL and the down-regulation of osteoprotegerin (OPG). Although RANKL is expressed in osteoblasts as well as osteocytes, RANKL derived from osteocytes plays a major role in the formation and activation of osteoclasts (OCL) in postnatal life. FGF23 secreted by osteocytes exerts its effects on distant targets in an endocrine manner. In the kidneys, FGF23 suppresses the expression of NaPi-IIa and NaPi-IIc to increase Pi excretion. Moreover, FGF23 reduces the expression of 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) and induces that of 25-hydroxyvitamin D-24-hydroxylase (24OHase). The resultant decrease in serum 1,25(OH)₂D level leads to the reduction in the intestinal Pi absorption. Animal studies have suggested that FGF23 also suppresses the secretion of PTH in the parathyroid glands and induces the expression of 24OHase in the placenta.