Osteocalcin modulates parathyroid cell function in human parathyroid tumors

Front Endocrinol (Lausanne). 2023 Mar 30:14:1129930. doi: 10.3389/fendo.2023.1129930. eCollection 2023.

Abstract

Introduction: The bone matrix protein osteocalcin (OC), secreted by osteoblasts, displays endocrine effects. We tested the hypothesis that OC modulates parathyroid tumor cell function.

Methods: Primary cell cultures derived from parathyroid adenomas (PAds) and HEK293 cells transiently transfected with the putative OC receptor GPRC6A or the calcium sensing receptor (CASR) were used as experimental models to investigate γ-carboxylated OC (GlaOC) or uncarboxylated OC (GluOC) modulation of intracellular signaling.

Results: In primary cell cultures derived from PAds, incubation with GlaOC or GluOC modulated intracellular signaling, inhibiting pERK/ERK and increasing active β-catenin levels. GlaOC increased the expression of PTH, CCND1 and CASR, and reduced CDKN1B/p27 and TP73. GluOC 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 in normal and tumor parathyroids at membrane or cytoplasmic level in cells scattered throughout the parenchyma. In PAds, the membrane expression levels of GPRC6A and its closest homolog CASR positively correlated; GPRC6A protein levels positively correlated with circulating ionized and total calcium, and PTH levels of the patients harboring the analyzed PAds. Using HEK293A transiently transfected with either GPRC6A or CASR, and PAds-derived cells silenced for CASR, we showed that GlaOC and GluOC modulated pERK/ERK and active β-catenin mainly through CASR activation.

Conclusion: Parathyroid gland emerges as a novel target of the bone secreted hormone osteocalcin, which may modulate tumor parathyroid CASR sensitivity and parathyroid cell apoptosis.

Keywords: CASR; ERK; GPRC6A; beta-catenin; osteocalcin; parathyroid tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HEK293 Cells
  • Humans
  • Osteocalcin / metabolism
  • Parathyroid Glands* / metabolism
  • Parathyroid Neoplasms* / pathology
  • Receptors, Calcium-Sensing / metabolism
  • beta Catenin / metabolism

Substances

  • Osteocalcin
  • beta Catenin
  • Receptors, Calcium-Sensing

Grants and funding

This work was supported by “Bando SIOMMMS 2018 Giovani Ricercatori” for the project “Expanding the crosstalk between bone and parathyroids: analysis of the osteocalcin receptor GPRC6A and of the potential interaction with the calcium sensing receptor in human parathyroid cells” to CV, by “Bando CARIPLO sulla ricerca biomedica legata alle malattie dell’invecchiamento 2018” for the project OSTMARK (no.2018-0458) to SC and GL, and by Italian Ministry of Health.