Osteocalcin in bone metabolism and aging: molecular mechanisms and biomarkers of the bone‐energy crosstalk (OstMARK)
ProjectOsteocalcin (OC) is a 49-aa peptide with multiple biological roles, spanning from regulation of bone mineralization, to biomarker of bone turnover, and metabolic hormone. As a hormone, OC displays tissue-specific expression, circadianicity, synthesis as pre-pro-molecule. Vitamin K is a cofactor involved in the carboxylation of 3 glutamate residues (Glu→Gla) of OC. The extra-skeletal biological effects (e.g., on pancreatic β-cells, adipocytes, myocytes) of OC depend upon its carboxylation hence, bone metabolism affects several homeostatic aspects (e.g., glucose and energy metabolism, muscular function).
Aging is linked to sarcopenia, metabolic dysfunctions, and increased fracture risk; OC could have a key role in this frailty syndrome.
To date, the detailed molecular mechanisms underlying OC activity are still unknown. The G protein-coupled receptor (GPRC6A), putative receptor for OC, is widely expressed and is activated by unrelated ligands. GPRC6A- and OC-null mice share the metabolic phenotype but differ by bone phenotype suggesting the existence of additional receptors. Also the relative endocrine role of GlaOC and GluOC is unknown: evidences in mice suggesting a major role of GluOC on energy metabolism contrast with the lack of any evidence in humans about the real homeostatic relevance of OC.
Starting from the structural characterization and the quantification of the different forms of OC either resident within bone or circulating, the main goal of this proposal is to detail the molecular mechanisms of OC-mediated regulation of energy metabolism (i.e., identification of OC receptors, downstream pathways, biological effects), the clinical effects of anabolic treatment for bone (teriparatide (TPT), vitamin K), and its association with the pathophysiological mechanisms underlying the geriatric metabolic dysfunctions and the frailty syndrome.
Aging is linked to sarcopenia, metabolic dysfunctions, and increased fracture risk; OC could have a key role in this frailty syndrome.
To date, the detailed molecular mechanisms underlying OC activity are still unknown. The G protein-coupled receptor (GPRC6A), putative receptor for OC, is widely expressed and is activated by unrelated ligands. GPRC6A- and OC-null mice share the metabolic phenotype but differ by bone phenotype suggesting the existence of additional receptors. Also the relative endocrine role of GlaOC and GluOC is unknown: evidences in mice suggesting a major role of GluOC on energy metabolism contrast with the lack of any evidence in humans about the real homeostatic relevance of OC.
Starting from the structural characterization and the quantification of the different forms of OC either resident within bone or circulating, the main goal of this proposal is to detail the molecular mechanisms of OC-mediated regulation of energy metabolism (i.e., identification of OC receptors, downstream pathways, biological effects), the clinical effects of anabolic treatment for bone (teriparatide (TPT), vitamin K), and its association with the pathophysiological mechanisms underlying the geriatric metabolic dysfunctions and the frailty syndrome.