Parathyroid Hormone Signaling in Bone Metabolism

Parathyroid hormone (PTH) plays a central role in the regulation of calcium homeostasis and bone remodelling by modulating both bone formation and resorption. Secreted in response to hypocalcaemia, PTH binds the PTH/PTH-related peptide receptor type 1 on osteoblasts, osteocytes, stromal cells and T cells. Acute, intermittent PTH exposure favours osteoblastic survival and matrix deposition, enhancing bone mass, whereas chronic elevation promotes osteoclastogenesis through upregulation of receptor activator of NF-κB ligand (RANKL) and suppression of osteoprotegerin in stromal cells and osteoblasts. In osteocytes, PTH-mediated inhibition of sclerostin relieves Wnt signalling antagonism, further stimulating bone formation. Intracellularly, PTH receptor activation engages protein kinase A, influences salt-inducible kinase activity and regulates transcriptional co-regulators such as CREB-regulated transcription coactivators. The precise pattern of PTH exposure thereby determines the balance of anabolic and catabolic pathways, guiding skeletal adaptation during development, ageing and in metabolic disease.

Research from Nature Portfolio

Recent studies have pinpointed salt-inducible kinases (SIKs) as key modulators of PTH signalling in osteocytes. PTH-induced inhibition of SIK2 promotes nuclear translocation of histone deacetylases 4 and 5 as well as CRTC2, thereby suppressing sclerostin expression and enhancing RANKL transcription. Genetic or pharmacological inhibition of SIKs mimics many anabolic actions of PTH, and administration of a selective SIK inhibitor in vivo increases bone formation rates and trabecular bone mass. This work highlights SIKs as therapeutic targets for replicating the bone-building effects of PTH without systemic hormonal administration.

Parathyroid Hormone Signaling in Bone Metabolism publication trend

The graph below shows the total number of articles in parathyroid hormone signaling in bone metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Osteocyte: A mature bone cell embedded within the mineralised matrix, acting as a mechanosensor and regulator of remodelling.

PTH receptor type 1 (PTHR1): A G-protein-coupled receptor mediating PTH and PTHrP signals in bone and kidney cells.

Salt-inducible kinase (SIK): A family of kinases that modulate transcriptional regulators in response to PTH signalling.

Sclerostin: A protein produced by osteocytes that antagonises Wnt/β-catenin signalling and inhibits bone formation.

RANKL: A cytokine expressed by osteoblasts and osteocytes that binds RANK on osteoclast precursors to stimulate bone resorption.

References

1. Reversal of the diabetic bone signature with anabolic therapies in mice. Bone Research (2023).
2. Comparative study in estrogen-depleted mice identifies skeletal and osteocyte transcriptomic responses to abaloparatide and teriparatide. JCI Insight (2023).
3. PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche. Cells (2024).
4. SIKs control osteocyte responses to parathyroid hormone. Nature Communications (2016).
5. Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes. PLOS ONE (2008).
6. Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH*. Journal of Biological Chemistry (2013).
7. Parathyroid Hormone Stimulates Receptor Activator of NFκB Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of cAMP-response Element-binding Protein*. Journal of Biological Chemistry (2002).
8. Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss. PLOS ONE (2010).