The orally available SIK2/SIK3 inhibitor SK-124 increases bone mass in hypogonadal male mice

TL;DR

A new drug called SK-124, which inhibits SIK2/SIK3, prevents bone loss in male mice with hypogonadism, suggesting it could be a treatment for osteoporosis.

Contribution

Demonstrates that SK-124, an orally available SIK2/SIK3 inhibitor, prevents bone loss in a hypogonadal mouse model.

Findings

SK-124-treated hypogonadal mice showed reduced bone loss compared to controls.

SK-124 increased bone turnover in a PTH-like manner.

RNA-sequencing revealed new pathways linked to bone formation in response to SK-124.

Abstract

At present, there are no FDA-approved orally-available bone anabolic agents to treat osteoporosis. PTH stimulates bone formation through an intracellular signaling cascade that involves the inhibition of salt-inducible kinase (SIK) isoforms 2 and 3. Therefore, direct small molecule SIK2/SIK3 inhibitors may represent a strategy to mimic PTH actions to treat different forms of osteoporosis. We previously described the synthesis and characterization of SK-124, a pharmacologic SIK2/SIK3 inhibitor that increases trabecular bone formation in eugonadal mice. However, the efficacy of this agent in osteoporosis mouse models remains unknown. Hypogonadism is an important cause of age-related bone loss. In this study, we investigated the therapeutic potential of SK-124 in a male hypogonadal bone loss model (orchiectomy, ORX) in BALB/c mice. Radiographic and histological analyses revealed that SK-124-treated ORX mice showed reduced bone loss compared to the vehicle-treated ORX mice. Serum bone turnover markers demonstrated that SK-124 treatment increased bone turnover, suggesting that SK-124 acts in a PTH-like manner in ORX mice. Bone RNA-sequencing analysis demonstrated novel pathways associated with increased bone formation in response to SK-124 treatment. These findings indicate that SK-124 prevents bone loss in a hypogonadal bone loss model and holds potential as an orally available therapeutic for treating osteoporosis due to testosterone deficiency.

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