BioProject

Over 6.8 million fractures are reported annually in the US, accounting for 20% of all musculoskeletal injuries. More...

Over 6.8 million fractures are reported annually in the US, accounting for 20% of all musculoskeletal injuries. Approximately 10% of fractures will experience delayed- or non-union. Parathyroid hormone (PTH) analogs and anabolic osteoporosis therapeutics can stimulate fracture repair in animal models and patients with chronic nonunion. Previous studies have demonstrated that small molecule salt inducible kinase (SIK) inhibitors mimic PTH action in vitro and in vivo. Therefore, we hypothesize that YKL-05-099, a small molecule SIK inhibitor, will accelerate fracture callus osteogenesis. Overall design: 126 nine-week-old female C3H/HeJ slow fracture healing mice underwent unilateral intramedullary femoral shaft pinning and a midshaft fracture. Thereafter, animals received daily subcutaneous injections of vehicle (PBS), YKL-05-099 (15mg/kg), or PTH 1-34 (100μg/kg). Mice were euthanized at 10, 14, and 21 days postoperatively. The callus tissues were assessed by RT-qPCR to detect fracture repair marker genes. Additionally, early time points were evaluated histologically and through single-cell RNA-Seq. μCT images were obtained for image-based callus analysis. Three-point bending testing was conducted on a group of femurs to evaluate tissue biomechanics. A hydrogel-based system for delivering PTH and nanoparticles containing SIK2 and SIK3 siRNAs was developed and tested in vitro and in vivo (N=32). Less...