# The Potential of Indole Alkaloids in Bone Health and Osteoporosis Management
## 5 Indole Alkaloids
### Harmine  
As an alkaloid of \(\beta\)-carbolines with a tricyclic pyrido[3,4-b] indole structure, harmine (7-methoxy-1-methyl-9\(H\)-pyridylo[3,4-b]indole) (**15**) (Figure 7) has been shown to have a variety of pharmacological effects in vitro and _in vivo_, including vasorelasxant and antidepressant effects as well as improved insulin sensitivity [70,71]. Harmine has several traditional medicinal uses and pharmacological activities such as anti-inflammatory, anti-parasitic, anti-tumor, and anti-diabetes properties. Uygur medicine in China uses different preparations of harmine to treat rheumatoid arthritis [72]. A mini library of indole derivatives was the focus of research by [PERSON] et al. (2011) [73]. These derivatives included harmine (**15**), harmol (1-methyl-2,9-dihydroxyrido [3,4-b]indol-7-one) (**13**), harmane (1-methyl-9\(H\)-pyridylo[3,4-b]indole) (**14**), harmaline (7-methoxy-1-methyl-4,9-dihydroxy-0\(H\)-pyridylo[3,4-b]indole) (**15**), and harmalol (1-methyl-4,9-dihydro-3\(H\)-pyridylo[4,3-b]indol-7-ol) (**16**), among others. Researchers have looked at how harmine and its derivatives (Figure 7) affect osteoclastogenesis in order to evaluate the relationship between the chemical structure and action of harmine. They found that harmol has similar effects to harmine in inhibiting RANKL-induced TRAP activity. After analyzing harmine and its derivatives, researchers found that harmine reduces osteoclastogenesis in RAW264.7 murine macrophage-like cells (Figure 7). According to these researchers, harmine prevented osteoclast differentiation in RAW 264.7 cells while preserving cell viability. It also prevented progenitor cells from differentiating into mononuclear osteoclasts and from fusing into multinucleated osteoclasts. The study employed primary BMMs and co-culture systems to confirm the inhibitory effects of harmine on osteoclastogenesis. Given that harmine was able to decrease osteoclastogenesis in single cultures of RAW264.7 cells and BMMs without osteoblasts, their findings imply that harmine primarily works on osteoclast precursors rather than osteoblasts. Using both in vitro and ex vivo models, harmine was demonstrated to decrease bone resorption in  
Figure 7: Structure of harmine (**15**) and its derivatives (**16–19**). investigations. An analysis of mice with ovariectomies revealed that harmine inhibits bone loss in vivo in models of osteoporosis. An analysis of harmine and its derivatives' structure-activity relationship (SAR) on osteoclastogenesis revealed that a double bond between C3 and C4 and a methoxy or hydroxy group at position 7 in \(\beta\)-carboline structures are critical. Therefore, harmine inhibits the mRNA and protein expressions of c-Fos and NFATc1, crucial transcription factors for osteoclastogenesis, that are increased by RANKL. Specifically, TRAP, c-Src, Atp6v0d2, and cathepsin K are among the osteoclast-specific genes whose expressions are regulated by NFATc1 and which modulate osteoclast fusion, activation, and function [74]. In 2018, [PERSON] et al. [75] created an oil-in-water harmine emulsion and found that the oral administration of harmine in an emulsion form reduced harmine accumulation in the mouse brain and that the intragastric administration of a harmine emulsion provoked bone-sparing effects in OVX-induced osteopororotic mice. These findings were made in the light of harmine's low bioavailability and potential side effects (an intraperitoneal injection of harmine can cause side effects in the central nervous system) [76; 77; 78]. Moreover, quantities of harmine were found in mouse bone marrow following oral treatment, which may account for the bone-protective effects observed in OVX mice. Consequently, their research validates that the intragastric delivery of a harmine emulsion promotes the development of type H blood vessels and bone in osteopororotic mice while inhibiting the creation of osteoclasts and enhancing preosteocalst PDF-BB-induced angiogenesis.