A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases

Abstract

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs' adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.

Keywords: bioactive compounds; bone diseases; bone remodeling; bone signaling pathways; natural products; osteoprotective properties.

Figure 1

Risk factors for BDs.

Figure 2

Molecular mechanism of bone resorption and the signaling pathways involved. SASP—senescence-associated secretory phenotype; SOST—sclerostin; DMP-1—dentin matrix acidic phosphoprotein 1; HIF-1—hypoxia-inducible factor 1; NOX-1/2—NADPH oxidase 1/2; cyt c—cytochrome C; ROS—reactive oxygen species; AGE/RAGE—advanced glycated end-products/receptor; HMGB1—high mobility group box 1; PTH—parathyroid hormone; AMPK—AMP-dependent kinase, PGC-1α—peroxisome proliferator-activated receptor gamma coactivator 1-alpha, tumor necrosis factor alpha; NF-ĸb—nuclear factor kappa B; TNF-α—tumor necrosis factor-alpha; p38 MAPK—mitogen-activated protein kinase; PGE2—prostaglandin E2, FasL—Fas ligand; IL-1b/6—interleukin 1 beta; IL-6—interleukin 6; VEGF-A—vascular endothelial growth factor alpha; CTSK—cathepsin K; IFN-γ—interferon gamma; CTR—calcitonin receptor, PI3K—phosphoinositide 3-kinase; Akt—protein kinase-B; GSK3β—glycogen synthase kinase-3β; JNK—c-Jun N-terminal kinase; ERK—extracellular signal-regulated kinase; tumor necrosis factor alpha; NF-ĸb—nuclear factor kappa B; TNF-α—tumor necrosis factor-alpha; p38 MAPK—mitogen-activated protein kinase.

Figure 3

Modulation of bone remodeling by natural products via Keap-1/Nrf2 signaling pathway. Bone loss caused by oxidative stress due to an imbalance in the antioxidant and free radicals in the system can be alleviated by natural products with antioxidant ability. Natural products promote the cytosol-to-nuclear translocation of Nrf2 (when detached from its repressor, Keap-1, during increased ROS generation) to interact with its operator, ARE, to induce the expression of antioxidant enzymes. Increased availability of antioxidant enzyme will hence scavenge the ROS and prevent ROS-mediated bone loss. Abbreviations: GCS—γ-glutamylcysteine synthetase; HO-1—heme oxygenase-1; NQO1—NAD(P)H:quinone reductase; Keap-1—Kelch-like ECH-associated protein 1; Nrf2—nuclear factor E2-related factor 2; ARE—antioxidant response element; GPx—glutathione peroxidase; GST—glutathione-S-transferase; CAT—catalase; DEX—dexamethasone.

Figure 4

Summary of signaling pathways through which natural products exert their osteoprotective properties, in addition to the Keap-1/Nrf2 signaling pathway. OPG—osteoprotegerin; NFATc-1—nuclear factor of activated T-cells cytoplasmic 1; CaMKII—Ca²⁺/calmodulin (CaM)-dependent protein kinases; IFN-γ—interferon gamma; AP-1—activator protein 1; ATP6v0d2—ATPase Hþ transporting V0 subunit d2; CTR—calcitonin receptor; OSCAR—osteoclast-associated receptor; TRAF6—tumor necrosis factor (TNF) receptor-associated factor-6; TRAP—tartrate-resistant acid phosphatase; RANKL—receptor activation of NF-κB ligand; M-CSF—monocyte/macrophage colony stimulating factor; MMP-9—matrix metalloproteinase-9; CTSK—cathepsin K; PI3K—phosphoinositide 3-kinase; Akt—protein kinase-B; GSK3β—glycogen synthase kinase-3β; JNK—c-Jun N-terminal kinase; ERK—extracellular signal-regulated kinase; tumor necrosis factor alpha; NF-ĸb—nuclear factor kappa B; TNF-α—tumor necrosis factor-alpha; p38 MAPK—mitogen-activated protein kinase.