Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice

Abstract

Excessive osteoclast (OC) activity together with relatively weak osteoblast (OB) function are strongly connected to osteolytic diseases, including osteoporosis, tumor-induced osteolysis, and inflammatory bone erosion. Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge-derived natural inhibitor of protein kinases with previously reported antiosteoarthritis and anti-cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose-dependent inhibitory effects on RANKL-induced OC formation, bone resorption, and OC-specific gene expression. These strong inhibitory effects were achieved by blocking the NF-κB and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3β (GSK-3β)/β-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx-2 expression, the main transcription factor in this pathway. Increased expression of Runx-2 was also correlated with expression of the OB-specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL/6j mouse model of ovariectomy (OVX)-induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC-related osteolysis and enhancing OB-induced ossification, suggesting the potential application of HMD in osteoporosis treatment.

Bi-directional regulation functions of lanthanum-substituted layered double hydroxide nanohybrid scaffolds via activating osteogenesis and inhibiting osteoclastogenesis for osteoporotic bone regeneration

“…Under the stimulus of upstream signaling, β-catenin accumulated in the cytoplasm and subsequently translocated to the nucleus, which brought about downstream osteogenic-related genes transcription. The inhibition of GSK-3β was proven to restore the β-catenin level to some extent, and then facilitated osteogenesis differentiation of BMSCs 58 , 59 . The OVX-rat cranial defect model further proved that the La-LDH nanohybrid scaffolds promoted the in vivo formation of the collagenous and non-collagenous organic matrix compared to the LDH scaffolds (Figure 11 ).…”

Maackiain dampens osteoclastogenesis via attenuating RANKL‐stimulated NF‐κB signalling pathway and NFATc1 activity

“…Osteoclastogenesis assay was used routinely as reported 25 . In brief, BMMs were seeded into 96‐well plates at a density of 6 × 10 3 cells per well.…”

“…Osteoclastogenesis assay was used routinely as reported. 25 In brief, Then, cells were fixed with 2.5% glutaraldehyde, gently washed with PBS for twice and stained with TRAcP staining solution at 37°C for about 40 minutes. The cells of each group were photographed using an inverted light microscope, and osteoclast-like cells with multi-nuclei (with more than three nuclei) were scored.…”

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

“…Osteoporosis is a disease with a major impact, especially in the elderly population [ 45 ]. In this sense, Wang et al [ 42 ] studied the effect of hymenialdisine ( Figure 5 ; compound 41 ) in the bone health of mice. The authors observed that treated animals displayed lower levels of bone volume and trabecular thickness levels than nontreated animals.…”