SIKs control osteocyte responses to parathyroid hormone

Area of Science:

• Bone biology
• Endocrinology
• Molecular signaling

Background:

• Parathyroid hormone (PTH) regulates bone remodeling by acting on osteocytes.
• PTH influences sclerostin (SOST) and RANKL expression, key regulators of bone formation and resorption.
• The precise molecular mechanisms of PTH action in osteocytes are not fully elucidated.

Purpose of the Study:

• To investigate the role of salt-inducible kinases (SIKs) in mediating PTH signaling in osteocytes.
• To determine if SIK inhibition can replicate the skeletal effects of PTH.

Main Methods:

• Utilized cultured osteocytes and in vivo models.
• Assessed the effects of PTH and small molecule SIK inhibitors on HDAC4/5 and CRTC2 localization.
• Employed RNA sequencing (RNA-seq) to analyze gene expression changes.
• Administered the SIK inhibitor YKL-05-099 daily in vivo.

Main Results:

• PTH regulates osteocyte gene expression through SIK2-mediated phosphorylation and inhibition of HDAC4/5 and CRTC2.
• SIK inhibitors decrease HDAC4/5 and CRTC2 phosphorylation, promoting their nuclear translocation.
• SIK inhibition in osteocytes mimics PTH effects on gene expression.
• Daily treatment with YKL-05-099 significantly increased bone formation and bone mass.

Conclusions:

• A significant pathway for PTH signaling in osteocytes involves the inhibition of SIKs.
• Small molecule SIK inhibitors demonstrate therapeutic potential for mimicking PTH's anabolic skeletal effects.