Osteoblasts originate from mesenchymal stem cells (MSCs), which play a crucial role in bone development and formation (Hojo and Ohba, 2020). MSCs differentiate into osteoblasts, chondrocytes, or adipocytes in response to transcription factors. Runx-related transcription factor 2 (Runx2) is a crucial transcription factor for the differentiation of MSCs and pre-osteoblasts into osteoblasts with many targets and downstream regulators, including osterix (Osx) and Sp7(Komori, 2019). Runx2 also regulates the secretion of bone matrix proteins, such as osteocalcin (OCN) and type I collagen (COL1A1) (Ducy et al., 1997). A large body of evidence suggests that the apoptosis of osteoblasts under pathological conditions leads to an imbalance in bone formation–resorption, which is closely associated with the development of OP (Komori, 2016; Chen et al., 2018). Therefore, effective delay of osteoblast apoptosis or promoting osteoblast differentiation may be promising in preventing and treating OP.

CUR plays a role in bone formation by regulating the differentiation of osteoblasts. CUR promotes osteoblast proliferation and upregulates the expression of genes related to bone formation, including alkaline phosphatase (ALP), OCN, and Runx2 (Li et al., 2015; Bukhari et al., 2019). Notably, CUR combined with chasteberry (FLL) effectively promoted osteoblast-mediated bone formation (Bukhari et al., 2019). Furthermore, the knockdown of the β-catenin gene in mice revealed the inhibition of osteoblast differentiation while promoting the differentiation of MSCs toward adipocytes. This finding suggests that the wingless and int-1(Wnt)/β-catenin pathway is an essential regulatory pathway in bone formation (Song et al., 2012). Chen et al. demonstrated that CUR mainly upregulated the phosphorylation activity of glycogen synthase 3β (Gsk3β) to promote the nuclear translocation of β-catenin and thus exert osteoprotective effects (Chen et al., 2016b). Researchers are interested in CUR analogs because of their role in OP. Mawani et al. identified three CUR analogs with potential anti-osteoporotic activity in MG-63 cells (Mawani and Orvig, 2014). A novel CUR analog, UBS109, upregulated the expression of osteogenic-related genes in MC3T3-E1 cells and promoted the bone formation and mineralization in osteoblasts by activating Smad; hence, its chemical structure is associated with osteogenic differentiation (Yamaguchi et al., 2012).

CUR is a bioactive antioxidant that can efficiently scavenge intracellular ROS and free radical activity; as such, it is thought to be beneficial in improving and preventing OP (Pulido-Moran et al., 2016). Evidence suggests that oxidative stress (OS)-induced apoptosis of osteoblasts plays a crucial role in the pathogenesis of OP (Manolagas, 2010). Xin et al. placed MC3T3-E1 cells in a rotating wall vascular bioreactor (RWVB) to simulate a microgravity environment in vitro. They found that long-term exposure to microgravity increased the level of oxidative stress and promoted the increase in ROS content in cells. After CUR treatment, the ROS expression decreased and osteoblast differentiation was promoted (Xin et al., 2015). Gsk3β is a serine/threonine kinase involved in bone metabolism and mediates OS-induced apoptosis in osteoblasts by promoting the release of cytochrome c from mitochondria (Leevers et al., 1999; Mudher et al., 2001). Dai et al. found that CUR attenuates OS-induced apoptosis in osteoblasts by activating protein kinase B (Akt) to inactivate downstream Gsk3β phosphorylation (Dai et al., 2017). In addition, Gsk3β downregulates the expression of nuclear factor-like 2 (Nrf2), a key transcription factor for cellular antioxidant defense involved in apoptosis (Zhuang et al., 2019). Nrf2 has been suggested as a potential target to slow down the progression of skeletal degenerative diseases (Jiang et al., 2018; Olagnier et al., 2018). Li et al. demonstrated that CUR rescued mouse MC3T3-E1 pre-osteoblasts from damages caused by OS by inhibiting the Gsk3β/Nrf2 signaling pathway (Li et al., 2020). In an in vitro experiment, Chen et al. exposed osteoblasts to dexamethasone (Dex); the process induced massive apoptosis accompanied by a decrease in ERK phosphorylation levels. CUR treatment prevented Dex-induced OP by inhibiting osteoblast apoptosis and upregulating the extracellular regulated protein kinase (ERK) phosphorylation (Chen et al., 2016a). In conclusion, CUR can exert osteoprotective effects by promoting osteoblast differentiation and inhibiting apoptosis.

Osteoclasts originate from the monocyte-macrophage lineage and are the primary functional cells of bone resorption; they can break down bone minerals and degrade the organic bone matrix (Suda et al., 1999). In general, the differentiation of macrophages into osteoclasts depends on the secretion of bone marrow stromal cells (BMSCs) or osteoblasts to release signaling factors necessary for osteoclast formation; these factors include macrophage colony-stimulating factor (M-CSF) or nuclear factor receptor activator kappa B ligand (RANKL) (Pereira et al., 2018). RANKL is a crucial regulator of osteoclast differentiation and is expressed by bone marrow stromal cells, osteoblasts, and osteoclasts (Kim et al., 2020). It binds to the receptor activator of nuclear factor kappa B (RANK) on the membrane of osteoclast precursor cells and activates the corresponding pathways of osteoclastogenesis, such as mitogen-activated protein kinase pass (MAPK), protein kinase B (Akt), and nuclear transcription factor-κB (NF-κB); RANKL promotes the expression of other osteoclastic factors, such as a nuclear factor of activated T cells 1 (NFATc1) and c-fos (Takayanagi, 2005; Park et al., 2017). The enhanced osteoclast overactivity under pathological conditions, such as inflammatory stimuli, decreased the bone reduction in volume, resulting in OP(Locantore et al., 2020; Ratajczak et al., 2020). Therefore, inhibition of osteoclast activity and its related signaling pathways that mediate bone resorption has become potential therapeutic targets for the prevention and treatment of OP.

CUR plays a role in bone resorption by regulating the differentiation of osteoclasts. Bukhari et al. found that CUR combined with FLL significantly inhibited the proliferative activity of RAW264.7 cells (Bukhari et al., 2019). In addition, CUR blocked the differentiation of osteoclast precursors into osteoclasts by inhibiting the production of chemokine CCL3 (Liang Z. et al., 2020). Similarly, CUR ameliorated microgravity-induced bone loss by inhibiting reactive oxygen species production and decreasing osteoclast-related gene expression (Xin et al., 2015). Micro RNAs develop OP by mediating osteoclast-regulated bone resorption (Lee et al., 2021). Li et al. found that CUR inhibited osteoclast differentiation markers, including cathepsin K, matrix metalloprotein (MMP)-9, and MMP-13, by upregulating the expression of miR-365 (Li et al., 2015). RANKL also plays a crucial role in osteoclast differentiation and activation. RANKL knockout mice prevented bone loss during arthritis, suggesting that osteoclast bone resorption under inflammatory conditions depends on RANKL/RANK signaling (Zeng et al., 2020; Xia et al., 2022). Hence, the RANKL/RANK pathway is a key pathway for osteoclast formation and is expected to be a potential target for the treatment of OP. Oh et al. demonstrated that CUR treatment in a co-culture system reduced bone loss caused by increased osteoclasts by inhibiting interleukin-α (IL-1α)-induced RANKL expression in bone marrow mesenchymal stem cells (Oh et al., 2008). Similarly, Park et al. found a robust inhibitory effect of CUR analogs on RANKL-induced osteoclastogenesis by assaying tartaric acid-resistant acid phosphatase (TRAP) activity in mouse RAW264.7 cells (Hie et al., 2009; Park et al., 2011). Similarly, Yamaguchi et al. demonstrated that CUR analogs (ECMN909 and UBS109) significantly inhibited RANKL-induced NF-κB activity in osteoblast precursor RAW264.7 cells and blocked their differentiation into osteoclasts in vitro (Yamaguchi et al., 2012). However, whether autophagy can promote osteoclastogenesis remains controversial; CUR, an autophagy activator and osteoclastogenesis inhibitor, inhibits osteoclast activity. For the first time, Ke et al. explained the underlying mechanism behind this paradoxical effect. They confirmed that CUR prevented bone loss by inhibiting the stimulatory effect of RANKL on osteoclast autophagy (Ke et al., 2020).

As a multi-targeted polyphenol, CUR exerts osteoprotective effects by modulating osteoclast-mediated bone resorption-related pathways. The MAPK and NF-κB pathways are significant osteoclast pathways for formation (Takayanagi, 2005; Park et al., 2017). The increased activity of MAPK and NF-κB pathways under inflammatory conditions promotes osteoclast activity and function. Previous studies showed that elevated inflammatory responses and inflammatory factors are related to the development and progression of OP. Furthermore, the immunomodulation of macrophage polarization is a crucial OP mechanism (Singh et al., 2012). M0 macrophages are transformed into proinflammatory macrophages (M1 phenotype) in pathological environments, and proinflammatory chemokines are then released. The proinflammatory microenvironment will activate osteoclast signaling pathways, such as NF-kB, and induce the differentiation of hematopoietic monocytes/macrophages. Meanwhile, M2 macrophages secrete anti-inflammatory factors, promote the formation of an anti-inflammatory microenvironment, and inhibit the differentiation and formation of osteoclasts (Yuan et al., 2017; Bai et al., 2018; Mahon et al., 2018). High levels of proinflammatory factors are closely associated with osteoclast-mediated focal bone resorption (Silverman and Sternberg, 2012). Yang et al. demonstrated that CUR exerted immunomodulatory effects on macrophages by inhibiting inflammatory responses, reducing the release of inflammatory factors, and preventing osteoclast formation by improving Akt/NF-κB/NFATc1 signaling (Yang et al., 2020). Similarly, Kim et al. found that CUR inhibited osteoclastogenesis by upregulating the antioxidant enzyme glutathione peroxidase 4 (GPX4) and attenuating RANKL signaling. The anti-osteoclastogenic effect of CUR appears to be mediated by inhibiting the expression of MAPK and its downstream transcription factor NFATc1 (Kim et al., 2011). Thus, CUR could be helpful in anti-OP by inhibiting osteoclast activity and its mediated bone resorption.

The OVX model is the most commonly used animal model of postmenopausal OP. Estrogen inhibits osteoclast formation and differentiation by binding to the osteoclast precursor receptor (Birmingham et al., 2012; Li et al., 2012). When estrogen is deficient, it increases osteoclast activity and causes significant bone loss. Therefore, effective prevention of estrogen deficiency-induced increase in osteoclast activity and bone loss has potential for the treatment of OP.

CUR has well-documented functional applications and therapeutic potential in treating estrogen-deficient bone loss. OVX-induced bone loss may be associated with elevated ROS activity (Maggio et al., 2003). Kim et al. found that in a mouse model of OVX, continuous treatment with CUR (9.5 μg/g/d) for 8 weeks significantly inhibited OVX-induced bone loss by upregulating the antioxidant enzyme GPX-1 activity and reducing the formation of the bone resorption marker type I collagen C-terminal peptide (CTX-1) (Kim et al., 2011). Liang et al. evaluated the effect of oral CUR (200 mg/kg/d) on bone trabeculae in OVX mice. OVX caused bone loss by promoting the production of CCL3 in bone trabeculae, and the effect was effectively reversed by CUR (Liang Z. et al., 2020). However, Folwarczna et al. found that although continuous dietary CUR (10 mg/kg/d) for 4 weeks slightly improved the morphological parameters of bone tissues damaged by estrogen deficiency, it did not improve bone mineralization or bone strength (Folwarczna et al., 2010). Frank et al. designed three doses of CUR (1.5, 3, and 15 mg/kg) and studied their osteoprotective effects after spinal fusion in OVX rats. Although the results showed increased spinal bone mineral density (BMD) in all three CUR groups compared with the OVX group, the difference was not statistically significant (Cho et al., 2017). This lack of effect occurs possibly because CUR is less bioavailable and has a shorter half-life in animals, so small doses may not be helpful for the prevention or treatment of OP. Increasing the amount of CUR may have protective effects on bone reconstruction Figures 1, 2, 3, 4.

Several studies have shown the beneficial effect of high doses of CUR on bone turnover and the increased bone strength in a mature rat model of OVX-induced postmenopausal OP (French et al., 2008; Cho et al., 2013). Cho et al. measured the spine of OVX SD rats fed with a steady diet of CUR (10 or 50 mg/kg/d) for 4 or 8 weeks. Both doses of CUR attenuated the loss of spinal BMD and improved bone strength in rats. The high-dose group of CUR was significantly superior to the low-dose group in terms of anti-bone resorption and improving bone strength (Cho et al., 2013). Cho et al. also found that combining CUR with alendronate was superior to a single treatment in anti-bone resorption and improved bone mechanical strength (Cho et al., 2012). Considering that CUR has similar efficacy to estrogen, Hussan et al. compared its therapeutic effect (110 mg/kg/d) with that of ephemeris (100 ug/kg/d) for 8 weeks in OVX rats. The reduction in bone trabeculae and bone loss in OVX rats due to estrogen deficiency was reversed by CUR. Moreover, the therapeutic effect was superior to that of Bemelia (Hussan et al., 2012). Jiang et al. conducted a mechanistic study of CUR on estrogen deficiency-induced OP. The high expression of EZH2 and its regulation of bone resorption-related pathways might be involved in the pathogenesis of estrogen deficiency-induced OP (Jing et al., 2016). CUR supplementation (110 mg/kg/d) protected against OVX-induced OP by modulating the enhancer of zeste homolog 2 (EZH2)/Wnt/β-catenin pathway after 12 weeks (Jiang et al., 2021). However, most current in vivo studies on CUR in estrogen-deficient OP have been limited to superficial studies, and fewer studies have addressed its molecular mechanisms. In summary, CUR could be a potential candidate for the prevention and treatment of bone loss in postmenopausal OP.

GIOP is the most common form of secondary OP (Laurent et al., 2022). Reduced bone formation and increased bone fragility due to osteoblast apoptosis play a vital role in the pathogenesis of GIOP (Weinstein et al., 1998). Glucocorticoids can accelerate bone loss by promoting RANKL activity and osteoclast formation (Yao et al., 2008). Therefore, preventing the apoptosis of osteoblasts or accelerating the apoptosis of osteoclasts would be a promising therapeutic strategy for the treatment of GIOP.

CUR promotes bone formation and is thought to help improve GIOP. In a rat model of Dex-induced GIOP, Chen et al. found that the administration of CUR (100 mg/lg/d) increased the femurBMD, improved the bone trabecular structure in rats, and significantly reversed the Dex-induced apoptosis in femoral osteoblasts. In vitro results also showed that CUR protected osteoblasts from Dex-induced apoptosis by inhibiting the expression of pro-apoptotic proteins and upregulating the ERK pathway (Chen et al., 2016a). Furthermore, substantial evidence suggests that miRNAs are involved in the progression of GIOP (Liu et al., 2017). CUR may regulate miRNAs to ameliorate glucocorticoid-induced secondary OP. Li et al. found that CUR supplementation (200 mg/kg/d) improved gastroprotection in GIOP mice by upregulating tibial miR-365 expression and inhibiting the osteoprotegerin (OPG)/RANKL/RANK pathway in GIOP mice, which was considered a potential therapeutic target for the treatment of GIOP (Li et al., 2015). Osteoblast differentiation mediated by the Wnt/β-catenin pathway plays a crucial role in the pathogenesis of GIOP (Karner and Long, 2017). CUR activated the Wnt/β-catenin pathway to promote osteoblast proliferation and differentiation (Tiwari et al., 2014; Tiwari et al., 2016). Chen et al. observed that CUR treatment (100 mg/kg/d) significantly ameliorated the reduced bone mineral density and bone mineral loss in GIOP rats by modulating the Wnt/β-catenin pathway and attenuating osteoblast differentiation dysfunction in vitro (Chen et al., 2016a). Moreover, CUR has significantly inhibited osteoclast-mediated bone resorption by stimulating osteoclastic apoptosis (Yamaguchi et al., 2012; Ke et al., 2020). However, CUR has not been reported to play a role in the pathogenesis of GIOP by modulating osteoclast activity. Further studies are needed to confirm whether CUR modulates osteoclasts to exert an ameliorative role in GIOP. However, there have been no reports on CUR’s role in the pathogenesis of GIOP by modulating osteoclast activity, and further studies are still needed to confirm that CUR’s modulation of osteoclasts plays an ameliorative role in GIOP in the future. In conclusion, CUR may be a new therapeutic approach for the treatment of GIOP through osteoprotective effects.

In recent years, the adverse effects of diabetes on bone health have received much attention as researchers intensively studied diabetes and its complications (Murray and Coleman, 2019). DOPis a secondary OP characterized by a hyperglycemia-induced reduction in bone mineral density and impaired bone microarchitecture. Chronic hyperglycemia decreased the bone density in diabetic patients (Kurra et al., 2014). However, a specific drug for the clinical treatment of DOP has not been developed yet, and conventional pharmacological therapies, such as bisphosphonates, are ineffective in long-term use and have serious side effects. Therefore, a safer and more effective treatment must be developed.

CUR is a potential treatment for DOP because of its proven ability to protect bone structure and regulate blood lipid levels (Ren et al., 2020; Inchingolo et al., 2022). Evidence suggests that impaired osteogenic differentiation function and angiogenic capacity of BMSCs are essential mechanisms for the development of DOP (Jing et al., 2016; Liao et al., 2016). CUR elicited osteoprotective effects by repairing osteoblasts damaged by high glucose and the osteogenic differentiation of BMSCs (He et al., 2020; Chen et al., 2021). Fan et al. found that CUR pretreatment promoted BMSC-mediated osteogenic differentiation and angiogenic coupling in a high-glucose environment and prevented diabetes-induced bone loss by inhibiting the NF-κB pathway. Further in vivo results showed that CUR supplementation (100 mg/kg/d) prevented bone loss and promoted angiogenesis in DOP mice (Fan et al., 2022). In an insulin-dependent diabetic model, the elevated activity of osteoclast markers, such as TRAP, reduced diabetic bone mass (Hie et al., 2007). By contrast, CUR supplementation (120 mg/kg/d) inhibited the increase in bone resorption activity by suppressing TRAP activity and expression in diabetic rats (Hie et al., 2009). In addition, type 2 diabetic OP (T2DOP) has become the most common form of DOP; it can accelerate bone loss and lead to fractures (Leslie et al., 2012). Liang et al. found that CUR treatment (110 mg/kg/d) protected the bone microarchitecture and improved bone mechanical properties in T2DOP rats by modulating the TGFβ/Smad2/3 pathway (Liang Y. et al., 2020). CUR analogs have been extensively studied for their therapeutic effects on DOP. Novel modified CUR, namely, CMC2.24, promoted inflammation regression and reduced hyperglycemia-induced bone loss in diabetic rats (Deng et al., 2021). Hence, CUR and its analogs may alleviate diabetic OP in vivo and in vitro by exhibiting osteoprotective effects and modulating blood glucose levels.

The microgravity environment experienced during bed rest, braking, or prolonged spaceflight is a significant risk factor for disuse OP (Rolvien and Amling, 2022). Prolonged exposure to microgravity reduced bone mass due to increased activity of bone resorption and inhibition of bone formation (Pan et al., 2014). Given that experiments during spaceflight are costly and challenging to implement, the HLS rat model can be used to effectively simulate the effects on bone during prolonged bed rest and microgravity environments (Giangregorio and Blimkie, 2002). Exposing rats to HLS accelerated osteoclast differentiation and formation, leading to bone loss. Furthermore, bone loss induced by a microgravity environment may be associated with oxidative stress caused by elevated reactive oxygen activity (Sun et al., 2013). Hence, microgravity-induced oxidative stress is essential in developing disuse bone loss and is expected to be an important target for the treatment of OP.

CUR exerts osteoprotective effects due to its antioxidant properties. For example, in a rat model of HLS, Xin et al. found that CUR treatment (40 mg/kg/d) alleviated HLS-induced oxidative stress and prevented and restored microgravity-induced bone loss. Further in vitro results showed that CUR promoted osteogenic differentiation in the microgravity environment and significantly inhibited osteoclastogenesis (Xin et al., 2015). However, studies addressing the direct effects of CUR on HLS-induced oxidative stress are limited; in this regard, future studies are needed to confirm the osteoprotective results of CUR in disuse bone loss. The above studies suggest that CUR has the potential to prevent and treat disuse OP by inhibiting oxidative stress.