Chutani Kunal, Rai Nikhil, Sardar Anirban, Yadav Anupama, Rai Divya, Raj Anuj, Maji Bhaskar, Verma Shikha, Tripathi Ashish Kumar, Dhaniya Geeta, Hingorani Lal, Mishra Prabhat Ranjan, Trivedi Ritu
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Front Endocrinol (Lausanne). 2025 Apr 25;16:1540237. doi: 10.3389/fendo.2025.1540237. eCollection 2025.
This study shows that Fortified Withaferin A (FWA, 10% w/w) accelerates bone healing, advancing from the fibrovascular to bone remodeling stage within 12 days, compared to the typical 23-24-day healing time in rodents. FWA (10% w/w) outperformed parathyroid hormone (PTH) in osteoclast regulation and minimized recovery time, highlighting its potential as a therapeutic agent for bone health.
FWA (10% w/w) was administered orally at 125 mg·kg. A transverse osteotomy model was used to assess post-natal bone regeneration. Additionally, an estrogen-deficient model was employed to evaluate the therapeutic potential of FWA (10% w/w). Bone regeneration was validated through calcein incorporation, gene expression analyses, micro-CT imaging and mechanical testing. Pharmacokinetic profiling was used to determine plasma exposure and trough concentration.
FWA (10% w/w) effectively downregulated bone-resorbing genes, promoted anabolic responses, and reduced inflammation. It enhanced post-natal bone regeneration, likely via Runx-2 activation and modulation of osteogenic genes, alongside suppression of E3 ubiquitin-ligases Smurf1 and Smurf2, resulting in significantly enhanced callus formation and healing speed. Micro-CT revealed an enhanced callus area of ~95.14% within 12 days, compared to ~72.87% associated with normal healing. In the estrogen-deficient model, FWA (10% w/w) led to ~83.88% bone volume fraction at 23 days, exceeding the ~76.80% in controls and matching PTH effects. Material stiffness showed significant gains, with average Young's modulus rising from ~54 ± 1.03 MPa to ~63 ± 2.54 MPa. Pharmacokinetic profiling indicated plasma exposure at 226 ng/ml*hr and higher trough concentration at 24 hr, contributing to optimum therapeutic effectiveness.
These results demonstrate that FWA (10% w/w) could significantly enhance bone mineralization and healing, facilitating an earlier transition from fibrovascular tissue to bone remodeling. The enhanced results, such as increased healing, better callus formation, and improved mechanical properties, indicate that FWA (10% w/w) is a potential intervention for delayed healing, especially in osteoporotic fractures.
本研究表明，与啮齿动物典型的23 - 24天愈合时间相比，强化的睡茄内酯A（FWA，10% w/w）可加速骨愈合，在12天内从纤维血管阶段进入骨重塑阶段。FWA（10% w/w）在破骨细胞调节方面优于甲状旁腺激素（PTH），并将恢复时间减至最短，凸显了其作为骨健康治疗药物的潜力。
以125 mg·kg的剂量口服给予FWA（10% w/w）。采用横向截骨模型评估出生后骨再生情况。此外，采用雌激素缺乏模型评估FWA（10% w/w）的治疗潜力。通过钙黄绿素掺入、基因表达分析、显微CT成像和力学测试验证骨再生情况。利用药代动力学分析确定血浆暴露量和谷浓度。
FWA（10% w/w）有效下调骨吸收基因，促进合成代谢反应并减轻炎症。它可能通过激活Runx - 2和调节成骨基因，同时抑制E3泛素连接酶Smurf1和Smurf2来增强出生后骨再生，从而显著增强骨痂形成和愈合速度。显微CT显示，12天内骨痂面积增加约95.14%，而正常愈合情况下为约72.87%。在雌激素缺乏模型中，FWA（10% w/w）在23天时导致骨体积分数约为83.88%，超过对照组的约76.80%，与PTH的效果相当。材料刚度显著增加，平均杨氏模量从约54 ± 1.03 MPa升至约63 ± 2.54 MPa。药代动力学分析表明血浆暴露量为226 ng/ml*hr，24小时时谷浓度更高，有助于达到最佳治疗效果。
这些结果表明，FWA（1）0% w/w）可显著增强骨矿化和愈合，促进从纤维血管组织到骨重塑的更早转变。愈合增加、骨痂形成更好以及力学性能改善等增强的结果表明，FWA（10% w/w）是延迟愈合尤其是骨质疏松性骨折的潜在干预措施。
