Abstract
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.
Highlights
Osteoporosis is a major problem in our aging population, with significant health and economic burden associated with fragility fractures [1]
We noted that salt inducible kinases (SIKs) deficient osteoclasts were susceptible to the inhibitory effects of both the potent/selective CSF1R inhibitor PLX-5622 [46] and YKL-05-099 (Figure 8H, I, Figure 8-figure supplements 2 and 3). These results demonstrate that YKL-05-099 can 432 block M-CSF action in myeloid cells, serving as a likely explanation for the anti433 resorptive effect seen with this agent in vivo. 434 435 Discussion Anti-resorptive therapies have long represented first line treatment for patients with osteoporosis
In addition to stimulating bone formation, YKL-05-099 452 treatment inhibits bone resorption. This appealing combination of anabolic and anti453 resorptive effects is, to date, only seen with the biologic agent romosozumab [50], an anti-sclerostin antibody whose widespread use is limited due to risk of increased cardiovascular events [51]. 457 In this study, we investigated mechanisms underlying the in vivo effects of YKL-05-099 treatment, and compared these results with those obtained following post-natal, ubiquitous Sik2/3 gene deletion. While both organismal perturbations led to increased bone formation and increased trabecular bone mass, key differences were observed
Summary
Osteoporosis is a major problem in our aging population, with significant health and economic burden associated with fragility fractures [1]. Genetic deletion of SIK2 and SIK3 in osteoblasts and osteocytes dramatically increases trabecular bone mass and causes phenotypic and molecular changes in bone similar to those observed with constitutive PTH receptor action [11]. We tested YKL-05-099 in female mice rendered hypogonadal by surgical oophorectomy and observed increased trabecular bone mass, increased bone formation, and reduced bone resorption Despite these beneficial effects, toxicities of hyperglycemia and nephrotoxicity were noted. Post-natal SIK2/3 gene deletion caused dramatic bone anabolism without hyperglycemia or BUN elevation, indicating that these side effects were due to inhibition of SIK1 or other targets of YKL144 05-099. Consistent with these results, YKL150 05-099 blocked M-CSF action in myeloid cells Taken together, these findings demonstrate that the dual target specificity of YKL-05-099 allows this multi-kinase inhibitor to uncouple bone formation and bone resorption. These findings demonstrate that the dual target specificity of YKL-05-099 allows this multi-kinase inhibitor to uncouple bone formation and bone resorption. 154
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