Osteoarthritis (OA) is a typical joint disease associated with chronic inflammation. The nuclear factor-kappaB (NF-κB) pathway plays an important role in inflammatory activity and inhibiting NF-κB-mediated inflammation can be a potential strategy for treating OA. Flavonoids are a class of naturally occurring polyphenols with anti-inflammatory properties. Structurally, natural flavonoids can be divided into several sub-groups, including flavonols, flavones, flavanols/catechins, flavanones, anthocyanins, and isoflavones. Increasing evidence demonstrates that natural flavonoids exhibit protective activity against the pathological changes of OA by inhibiting the NF-κB signaling pathway. Potentially, natural flavonoids may suppress NF-κB signaling-mediated inflammatory responses, ECM degradation, and chondrocyte apoptosis. The different biological actions of natural flavonoids against the NF-κB signaling pathway in OA chondrocytes might be associated with the differentially substituted groups on the structures. In this review, the efficacy and action mechanism of natural flavonoids against the development of OA are discussed by targeting the NF-κB signaling pathway. Potentially, flavonoids could become useful inhibitors of the NF-κB signaling pathway for the therapeutic management of OA.

Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, and glycolipid metabolism. ATF4 induces the differentiation of bone marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, and inhibits osteoclast formation, promoting bone formation and remodeling. In addition, ATF4 mediates the energy metabolism in osteoblasts and promotes angiogenesis. ATF4 is also involved in the mediation of adipogenesis. ATF4 can selectively accumulate in osteoblasts. ATF4 can directly interact with RUNT-related transcription factor 2 (RUNX2) and up-regulate the expression of osteocalcin (OCN) and osterix (Osx). Several upstream factors, such as Wnt/β-catenin and BMP2/Smad signaling pathways, have been involved in ATF4-mediated osteoblast differentiation. ATF4 promotes osteoclastogenesis by mediating the receptor activator of nuclear factor κ-B (NF-κB) ligand (RANKL) signaling. Several agents, such as parathyroid (PTH), melatonin, and natural compounds, have been reported to regulate ATF4 expression and mediate bone metabolism. In this review, we comprehensively discuss the biological activities of ATF4 in maintaining bone homeostasis and inhibiting OP development. ATF4 has become a therapeutic target for OP treatment.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration. Autophagy is associated with chondrocyte homeostasis and exhibits a role in protecting against OA pathogenesis. Geniposide (GEN), an iridoid glycoside extracted from Eucommia ulmoides Oliv, acts as an activator of GLP-1R, which can stimulate autophagy. The AMPK/mTOR signaling pathway participates in the mediation of autophagy, and GLP-1R may act as an upstream factor of AMPK. However, whether GEN mediates the autophagic responses by activating the GLP-1R/AMPK/mTOR signaling pathway in OA chondrocytes is still unclear. In the current study, attenuated autophagy in MIA-induced rat OA models was observed, as shown by up-regulated expression of p62 and down-regulated expression of Beclin-1 and LC3-II/I. GEN stimulated autophagy and protected OA cartilage by up-regulating GLP-1R expression. In addition, GEN could enhance AMPK phosphorylation and down-regulate mTOR expression in IL-1β-treated C28/I2 cells. Inhibition of AMPK or activation of mTOR could reverse the stimulatory effects of GEN on autophagy. Furthermore, a GLP-1R inhibitor Exendin 9-39 could eliminate the chondroprotective effects of GEN by suppressing the AMPK/mTOR signaling pathway. Conclusively, Geniposide exhibits protective effects against osteoarthritis development by stimulating autophagy via activating the GLP-1R/AMPK/mTOR signaling pathway.

The endoplasmic reticulum (ER) is the main site for protein synthesis, folding, and secretion, and accumulation of the unfolded/misfolded proteins in the ER may induce ER stress. ER stress is an important participant in various intracellular signaling pathways. Prolonged- or high-intensity ER stress may induce cell apoptosis. Osteoporosis, characterized by imbalanced bone remodeling, is a global disease caused by many factors, such as ER stress. ER stress stimulates osteoblast apoptosis, increases bone loss, and promotes osteoporosis development. Many factors, such as the drug's adverse effects, metabolic disorders, calcium ion imbalance, bad habits, and aging, have been reported to activate ER stress, resulting in the pathological development of osteoporosis. Increasing evidence shows that ER stress regulates osteogenic differentiation, osteoblast activity, and osteoclast formation and function. Various therapeutic agents have been developed to counteract ER stress and thereby suppress osteoporosis development. Thus, inhibition of ER stress has become a potential target for the therapeutic management of osteoporosis. However, the in-depth understanding of ER stress in the pathogenesis of osteoporosis still needs more effort.

Osteoporosis (OP), characterized by an imbalance of bone remodeling between formation and resorption, has become a health issue worldwide. The receptor for advanced glycation end product (RAGE), a transmembrane protein in the immunoglobin family, has multiple ligands and has been involved in many chronic diseases, such as diabetes and OP. Increasing evidence shows that activation of the RAGE signaling negatively affects bone remodeling. Ligands, such as advanced glycation end products (AGEs), S100, β-amyloid (Aβ), and high mobility group box 1 (HMGB1), have been well documented that they may negatively regulate the proliferation and differentiation of osteoblasts and positively stimulate osteoclastogenesis by activating the expression of RAGE. In this review, we comprehensively discuss the structure of RAGE and its biological functions in the pathogenesis of OP. The research findings suggest that RAGE signaling has become a potential target for the therapeutic management of OP.

Bone and cartilage diseases are significantly associated with musculoskeletal disability. However, no effective drugs are available to cure them. FOXO3a, a member of the FOXO family, has been implicated in cell proliferation, ROS detoxification, autophagy, and apoptosis. The biological functions of FOXO3a can be modulated by post-translational modifications (PTMs), such as phosphorylation and acetylation. Several signaling pathways, such as MAPK, NF-κB, PI3K/AKT, and AMPK/Sirt1 pathways, have been implicated in the development of bone and cartilage diseases by mediating the expression of FOXO3a. In particular, FOXO3a acts as a transcriptional factor in mediating the expression of various genes, such as MnSOD, CAT, BIM, BBC3, and CDK6. FOXO3a plays a critical role in the metabolism of bone and cartilage. In this article, we mainly discussed the biological functions of FOXO3a in bone and cartilage diseases, such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and intervertebral disc degeneration (IDD). FOXO3a can promote osteogenic differentiation, induce osteoblast proliferation, inhibit osteoclast activity, suppress chondrocyte apoptosis, and reduce inflammatory responses. Collectively, up-regulation of FOXO3a expression shows beneficial effects, and FOXO3a has become a potential target for bone and cartilage diseases.