Salt inducible kinases and PTH1R action.

Parathyroid hormone is a central regulator of calcium homeostasis. PTH protects the organism from hypocalcemia through its actions in bone and kidney. Recent physiologic studies have revealed key target genes for PTH receptor (PTH1R) signaling in these target organs. However, the complete signal transduction cascade used by PTH1R to accomplish these physiologic actions has remained poorly defined. Here we will review recent studies that have defined an important role for salt inducible kinases downstream of PTH1R in bone, cartilage, and kidney. PTH1R signaling inhibits the activity of salt inducible kinases. Therefore, direct SIK inhibitors represent a promising novel strategy to mimic PTH actions using small molecules. Moreover, a detailed understanding of the molecular circuitry used by PTH1R to exert its biologic effects will afford powerful new models to better understand the diverse actions of this important G protein coupled receptor in health and disease.

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.