Parathyroids regulate bone metabolism through parathormone (PTH), while bone modulates parathyroid function through calcium and fibroblast growth factor 23. We tested the hypothesis that the bone matrix protein osteocalcin (OC), secreted by osteoblasts, modulates parathyroid function. In primary cell cultures derived from human parathyroid adenomas (PAds), incubation with g-carboxylated OC (GlaOC) or uncarboxylated OC (GluOC) modulated intracellular signaling pathways inhibiting pERK/ERK, and increasing active b-catenin levels, while pAKT/AKT levels were unaffected. GlaOC increased the expression of PTH, CCND1 and CASR, and reduced CDKN1B/p27 and TP73. GluOC also stimulated transcription of PTH, and inhibited MEN1 expression. Moreover, GlaOC and GluOC reduced staurosporin-induced caspase 3/7 activity. The putative OC receptor GPRC6A was detected at the membrane level in a fraction of cells and at cytoplasmic level in other cells scattered throughout the parenchyma in normal and tumor parathyroids. In PAds, the membrane expression levels of GPRC6A and its closest homolog CASR positively correlated, and GPRC6A levels positively correlated with plasma ionized calcium, serum total calcium and PTH levels of patients harboring the analyzed PAds. Silencing CASR expression in PAds-derived cells showed that GlaOC and GluOC modulated pERK/ERK and active b-catenin mainly through CASR activation. In HEK293A cells transfected with human GPRC6A or with CASR, GlaOC and GluOC can activate both receptors, but, while extracellular calcium ([Ca2+]o) is needed for CASR activation by GlaOC, GPRC6A can be activated by GlaOC and GluOC in a calcium-free medium as well as in presence of 5.0 mM [Ca2+]o, exerting an opposite effect to that observed in presence of 1.5 mM [Ca2+]o. Further, GlaOC and GluOC reduced the staurosporin-induced caspase 3/7 activity. In conclusion, OC emerges as an additional actor in the bone-parathyroid cross-talk, contributing to modulation of the parathyroid CASR sensitivity