Elevation of the unfolded protein response increases RANKL expression

Area of Science:

• Bone Biology
• Cellular Stress Response
• Endocrinology

Background:

• Increased receptor activator of nuclear factor kappa-B ligand (RANKL) drives pathologic bone loss.
• The unfolded protein response (UPR) is a cellular stress pathway activated by endoplasmic reticulum (ER) protein misfolding.
• The precise triggers for elevated RANKL in bone loss remain unclear.

Purpose of the Study:

• To investigate if the UPR pathway stimulates RANKL production in bone cells.
• To determine the role of UPR-induced RANKL in pathologic bone resorption.

Main Methods:

• Pharmacologic induction and inhibition of UPR in primary osteoblastic cells and cell lines.
• Gene silencing of proteins involved in ER-associated degradation (ERAD).
• Assessment of RANKL expression and bone resorption in murine calvarial cultures.
• In vivo studies involving tunicamycin administration to adult mice.

Main Results:

• Tunicamycin-induced UPR increased RANKL expression in osteoblasts and osteocytes.
• Inhibition of UPR reduced tunicamycin-induced RANKL production.
• Disruption of ERAD pathways elevated UPR and RANKL mRNA.
• Tunicamycin and hypoxia increased RANKL and bone resorption in calvarial cultures.
• In vivo, tunicamycin treatment led to ER dilation, elevated UPR, increased RANKL, and more osteoclasts.

Conclusions:

• Excessive UPR signaling in osteoblasts and osteocytes stimulates RANKL expression.
• UPR-mediated RANKL production contributes to excessive bone resorption and bone loss.
• Targeting the UPR pathway may offer a therapeutic strategy for bone loss conditions.