# The Potential of Indole Alkaloids in Bone Health and Osteoporosis Management
## 5 Indole Alkaloids
### Rutaocarpine  
Rutaacarpine (8,13-hydroindolo [2\({}^{\prime}\),3\({}^{\prime}\);3,4])pyrido[2,1-b]quinazolin-5(7\(H\))-one) (14) (Figure 6) [62] is a bioactive alkaloid that was isolated from the adaptable medicinal herb _Evodia rutaacarpa_. In China, this herb is used clinically to treat amenorrhoea, headache, stomach pain, diarrhea, and postpartum hemorrhage.  
Rutaacarpine, one of _Evodia_ rutaacarpa's most characteristic indolopyridoquinazoline alkaloids, has a wide range of pharmacological applications in the treatment of metabolic, cerebrovascular, and cardiovascular illnesses.  
In 2024 [63], [PERSON] et al. reported on the effects of rutaacarpine on promoting osteoblast development in hBMCs. Specifically, rutaacarpine induced the expression of genes linked to osteogenesis, including ALP, OC, ON, and RUNX2, which are crucial for the maturation of osteogenic processes, matrix mineralization, and the control of transcription factors that are essential for the development of bones and osteogenesis [64]. Their rutaacarpine therapies resulted in an upregulation of COMP, another osteogenic gene marker. Through the activation of BMP2 and ALP activity, COMP has been demonstrated in an ectopic bone formation rat model to improve osteogenesis [65].  
The activation of the FAK pathway by rutaacarpine is essential for the stimulation of osteogenesis and bone formation. Another route that is increased when rutaacarpine is exposed to hBMCs is TGF\(\beta\). Through the SMAD signaling pathway, TGF\(\beta\) recruits stromal stem cells to the bone resorption process and controls the maintenance of postnatal bone and cartilage. Osteoblasts' production of new bone and osteoclastogenesis's induction of bone degradation are linked by TGF\(\beta\)[66].  
A key signaling role for TGFb isoforms and their receptors, such as TGF\(\beta\)R2, is played in the development of bones. In their investigation, the downregulation of rutaacarpine's osteogenic induction effects was caused by the inhibition of the TGF\(\beta\) pathway. Rutaacarpine was found to also upregulate the Toll-like receptor signaling pathway. Following rutaacarpine treatments, oxidative stress and selenium pathways are also activated in  
Figure 6: Structure of rutaacarpine (14).  
hBMSCs, suggesting rutaecarpine's preventive antioxidant effect against age-related bone loss. These findings suggest that rutaecarpine may have a therapeutic benefit by lowering senescent cells and preventing age-related bone loss.  
Furthermore, ex vivo organotypic cultures of embryonic chick femurs treated with rutaecarpine demonstrated the beneficial effects of this chemical on metrics related to bone, such as cortical thickness and BV/TV. The potential of rutaecarpine to shield rats against OVX-induced bone loss has also been studied. Rutaecarpine treatments of OVX mice for three months resulted in improved bone density, probably as a result of mechanisms related to osteoproteger induction [67].  
Anti-osteoporotic medication use may raise the risk of cardiovascular illnesses, myocardial infarction, and stroke [68]. Both men and women with cardiovascular disorders typically have lower bone mass densities. Rutaecarpine has been studied previously for its beneficial effects as an antioxidant and an inflammatory modulator that lower the risk of heart disorders [69]. In conclusion, their research shows that rutaecarpine plays protective roles in promoting bone formation by raising the osteoblast differentiation potential of hBMSCs and lowering oxidative stress and senescent cell load.