Figure 2:

PTH signaling in osteocytes inhibits SIK2 activity via protein kinase A-mediated phosphorylation. By reducing SIK activity, PTH reduces phosphorylation levels of SIK substrates including class IIa HDACs and CRTC family members. Upon dephosphorylation, these factors translocate to the nucleus. Class IIa HDACs block MEF2C-driven SOST expression. CRTC2 stimulates RANKL expression driven by CREB and other bZIP family transcription factors. Small molecule SIK inhibitors such as YKL-05–099 mimic the actions of PTH, both in vitro and in vivo. As schematized here, SIK inhibition represents an intracellular mechanism to ensure that PTH signaling stimulates both bone formation and bone resorption.