Skip to main content
Download PDF

The potential role of herbal extract Wedelolactone for treating particle-induced osteolysis: an in vivo study

Journal of Orthopaedic Surgery and Research volume 17, Article number: 335 (2022) Cite this article

Abstract

Background

Osteolysis is one of the most prevalent clinical complications affecting people who undergo total joint replacement (TJR). Wedelolactone (WDL) is a coumestan compound derived from the Wedelia chinensis plant and has been demonstrated to exhibit anti-inflammatory properties. This study aimed to investigate the oral administration of WDL as a potential treatment for particle-induced osteolysis using a well-established mice calvarial disease model.

Methods

Thirty-two C57BL/6 J mice were randomized into four groups: Sham, vehicle, osteolysis group with oral WDL treatment for 4 weeks (WDL 4w), and osteolysis group treated for 8 weeks (WDL 8w). Micro-CT was used to quantitatively analyze the bone mineral density (BMD), bone volume/tissue volume (BV/TV) and trabecular bone thickness (Tb.Th). Osteoclast numbers were also measured from histological slides by two investigators who were blind to the treatment used.

Results

The results from micro-CT observation showed that BMD in the WDL 8w group improved significantly over the vehicle group (p < 0.05), but there was no significant difference between WDL 4w and 8w for BV/TV and Tb.Th. Osteoclast numbers in the WDL 4w group were also lower than the vehicle group (p < 0.05), but the difference between WDL 8w and 4w groups was not significant.

Conclusions

Particle-induced osteolysis is an inevitable long-term complication after TJR. The results of this animal study indicate that an oral administration of WDL can help reduce the severity of osteolysis without adverse effects.

Background

Artificial joint replacement (AJR) is considered an effective method of treating severe joint degeneration [1]. However, periprosthetic osteolysis resulting from the deposition of wear particles from the articulating joint is one of the major clinical complications following AJR [2]. Wear particles can stimulate inflammatory responses and osteoclastic resorption processes at the bone implant interface, which consequently often leads to implant loosening [3]. Although bearing materials have been introduced to reduce the generation of wear particles, osteolysis is still prevalent and is considered a major long-term complication of AJR.

Besides changing the base material of the implant, pharmaceuticals have also been investigated as a method for reducing osteolysis [4]. Bisphosphonates are well-known drugs for treating osteoporosis, but have also been shown to be effective at suppressing osteolysis [5, 6]. Similarly, statins, which are lipid-lowering agents, have been reported to reduce particle-induced osteolysis in a murine calvarial model [5]. However, such drugs can also introduce considerable serious side effects, such as atypical femoral bone fracture and osteonecrosis of the jaw [7,8,9].

Animal models are often used for investigating mechanisms that can lead to particle-induced osteolysis and for evaluating suitable treatment methods [5, 10,11,12,13,14]. A previous study by our institute investigated whether strontium ranelate (SR) [11], a drug for osteoporosis, could be effectively used to combat osteolysis. After gavage-feeding mice for up to 4 weeks, the results showed a significant increase in bone mineral density (BMD), bone volume/tissue volume (BV/TV) and trabecular thickness (Tb.Th), and a significant reduction in osteoclast numbers [11]. However, long-term use of SR may increase the risk of cardiovascular disease [15,16,17].

As an alternative to pharmaceuticals, Chinese herbal medicines are considered a more natural solution with fewer side effects [18]. The International Organization for Standardization has also assembled a technical committee (ISO/TC 249) to standardize medical fields derived from Chinese medicine. With the increasing popularity, more resources and attention have been given to the potential benefits for treating disease [19,20,21].

Wedelolactone (WDL) is a coumestan compound extracted from the Wedelia Chinensis plant [22]. WDL is considered a traditional Chinese herbal medicine with strong anti-inflammatory properties [23,24,25,26,27]. Recent studies have shown that WDL can promote hair growth [28] and is hepatoprotective [29, 30], neuroprotective [31] and anti-carcinogenic [32, 33]. However, few studies have reported on the potential of WDL for treating diseases of the skeletal system. Based on the ability of WDL to reduce inflammation [23,24,25,26,27] and inhibit osteoclastogenesis [34, 35], it is hypothesized that WDL could also play a role in reducing the risk of particle-induced osteolysis. This study used a well-established murine calvarial osteolysis model to investigate whether WDL administered orally could reduce the severity of osteolysis.

Methods

Establishing the calvarial particle-induced osteolysis model

The protocol for this experiment was approved by the Institutional Animal Care and Use Committee at the institute where the study was performed. Thirty-two 6-week-old C57BL/6 J female mice were supplied by BioLASCO (Taipei, Taiwan), an AAALAC certified biotechnology company. The animals were kept in a room at 24℃, 50% humidity, and with a 12 h light/dark cycle (light from AM 7:00 to PM 7:00). The animals were randomly separated into four groups: (1) sham group (n = 8) (underwent surgery only) (2) vehicle group (n = 8) (implanted with PS particles) [36,37,38], (3) WDL 4w (n = 8, implanted with PS particles and treated with WDL for 4 weeks. 7 animals remained at the end of the experiment) and (4) WDL 8w (n = 8, treatment for 8 weeks). The vehicle group and WDL-treated groups were injected with 1 mg PS particles/100 μl HA [10, 25]. The polystyrene particles (Polystyrene Latex Spheres, 610–38) were purchased from TED PELLA, Inc. (CA, USA). Three hundred particles were randomly selected and SEM was used to measure the particle size and aspect ratio (Fig. 1a). The particles were found to be 1.03 ± 0.04 μm and 0.99 ± 0.03, respectively (Fig. 1b, c). The particles were also confirmed to have an endotoxin level below 0.25 EU/mL using a Limulus Ambocyte Lysate assay kit (ToxinSensor™ gel clot endotoxin assay kit, GenScript, NJ, USA) and then suspended in hyaluronic acid.

Fig. 1
figure 1

SEM image (× 12,000) of polystyrene (PS) particles (a). The particle size distribution by light-scattering analysis (b). The particle size distribution (c) and the aspect ratio (d) of the particles from SEM images

Full size image

To inject the particles, the mice were anesthetized with 100 mg/kg of Zoletil 50 and 10 mg/kg Rompun by intraperitoneal injection. A 0.5 × 0.5 cm area of the middle calvaria was exposed by sagittal incision. After removing the periosteum intact, the particle suspension was spread over the area and the incision was closed with sutures. After 2 week post-surgery, the WDL 4w and 8w groups were gavage-fed with Wedelolactone (Y0001599, European Pharmacopoeia Reference Standard, Sigma-Aldrich, USA) at a dose of 4 mg/kg/day for 5 days/week [21]. WDL was dissolved by DMSO as stock solution and diluted with phosphate-buffered saline (PBS) into 10 volumes to attain a dosage of 4 mg/kg. The vehicle group was gavage-fed the vehicle solution (10% DMSO in PBS). The sham group, vehicle group and WDL 4w group were then sacrificed after 4 weeks of feeding either the vehicle or WDL, and the WDL 8w group was sacrificed after 8 weeks of feeding WDL.

Micro-CT imaging analysis

The calvarias were fixed in 10% buffered formalin for 24 h, and then transferred to 70% ethanol for 24 h. The specimens were scanned with the micro-CT system Skyscan 1076 (Bruker micro-CT, Kontich, Belgium) at a resolution of 2048 × 2048. Three-dimensional images were reconstructed in Skyscan with a voxel size of 9 μm [10, 25]. A spherical volume of interest (VOI) with a diameter of 5 mm was then defined with the bregma as the center. Within this VOI, the bone mineral density (BMD, mg/cc), the ratio of bone volume to tissue volume (BV/TV, %) and trabecular thickness (Tb.Th) were recorded for each group.

Histological analysis

The calvarias were decalcificated in 10% ethylenediaminetetraacetic acid (EDTA) for 2 weeks, and then embedded in paraffin. Each section with a thickness of 5 μm were taken in the sagittal plane centered over the particle-treated area. The sections were then stained with hematoxylin and eosin (H&E stain) to observe the morphology of cellular inflammatory responses from the connective tissue. A tartrate-resistant acid phosphatase (TRAP) stain was performed using a commercial TRAP kit (#386A, Sigma-Aldrich). The number of osteoclasts was determined by counting the number of TRAP-positive multinucleated cells by two coauthors to eliminate intra- and inter-observer error.

Statistical analysis

The data was analyzed using one-way analysis of variance (ANOVA) to show the difference between groups. Multiple comparisons were adjusted with a Bonferroni post hoc test. Results were reported as mean ± standard deviation (SD). Any p value less than 0.05 was considered significantly different.

Results

Micro-CT imaging analysis

A visual analysis of the three dimensional (3D) reconstructed micro-CT images showed clear differences between the sham group, vehicle group, and WDL groups (Fig. 2a). The images showed typical osteolysis with pores in the sham group, but both the size and number of pores decreased in WDL-treated groups. The presence of PS particles significantly decreased the BMD in the vehicle group by 7.8% when compared to the sham group (0.74 ± 0.03 for vehicle group and 0.801 ± 0.03 for sham group, p < 0.01). Both WDL groups showed an increase in BMD (Fig. 2b), with the 8w group showing a significant increase of 5.1% in comparison to the vehicle group (0.78 ± 0.01 for 8w group and 0.74 ± 0.03 for vehicle group, p < 0.05). The BV/TV in the vehicle group decreased by 4.1% in comparison to the sham group (21.23 ± 1.43 in vehicle group versus 22.1 ± 1.54 in sham group) but increased in the WDL 4w group (22.96 ± 2.07) and WDL 8w group (22.44 ± 2.78). However, there were no significant differences in BV/TV and Tb.Th between the WDL 4w and WDL 8w groups (Fig. 2b).

Fig. 2
figure 2

Reconstructed image of the VOI with the bregma at the center. The VOI is defined with a diameter of 5 mm (a). Micro-CT image of bone formation in a particle-induced osteolysis model measured at 4 and 8 weeks after feeding WDL (b) (*p < 0.05; ** p < 0.01, as determined using ANOVA testing)

Full size image

Histomorphometric analysis

Histological analysis with H&E staining was used to evaluate the inflammatory response. Pseudomembrane proliferation occurred in the vehicle and WDL groups. The morphology of the cells in the periosteum was observed to change to a circle-shaped contour, while the cells resembled a flat contour in the sham group. Multinucleated giant cells were found in the surrounding periosteum (Fig. 3). TRAP staining was used to highlight polymer particles in the periosteal cells and multinucleated giant cells (Fig. 4a, b).

Fig. 3
figure 3

Hematoxylin and eosin (H&E) staining of periosteum in mice calvarial section. Multinucleated giant cells were observed in the groups injected with PS particles (Magnification: × 40; scale bar: 100 μm)

Full size image
Fig. 4
figure 4

TRAP staining indicated that PS particles exist in the periosteal cells and multinucleated giant cells in mice calvarial tissue (a) (Magnification × 40 Scale bar: 100 μm). Different shapes of PS particles and melanin granules observed in TRAP staining. Arrow, PS particle; Arrow head, melanin granule (b) (Magnification × 100 Scale bar: 20 μm)

Full size image

Osteoclasts around the bone perimeter

TRAP stain was used to highlight osteoclasts around the calvaria to calculate the osteoclast numbers in each group. The results showed the osteoclast numbers in the vehicle group increased significantly in comparison to the sham group (43.7 ± 10.1 in vehicle group versus 18.2 ± 14.5 in sham group, p < 0.05), demonstrating that the polymer particles likely induced osteolysis. Furthermore, there was a significant reduction in osteoclast numbers in the WDL 4w group in comparison to the vehicle group (21.1 ± 9.8 in WDL 4w group versus 43.7 ± 10.1 in vehicle group, p < 0.05). However, osteoclast number in WDL 8w group (30.6 ± 4.0) was no significantly different to the WDL 4w group (Fig. 5b).

Fig. 5
figure 5

Typical samples from micro-CT with purple staining showing TRAP-positive osteoclasts (a) (Magnification: × 40; Scale bar: 100 μm). Average number of TRAP-positive cells from each group are presented as the mean ± SD (b) (*p < 0.05)

Full size image

Discussion

Osteolysis is one of the major long-term complications affecting patients who undergo AJR. Chinese herbal medicine is generally considered to be milder than pharmaceutical treatments and does not produce strong adverse effects. This study aimed to investigate the potential use of the Chinese herbal medicine wedelolactone for reducing the incidence of particle-induced osteolysis.

Bisphosphonates (BPs) are commonly used to treat conditions of metabolic bone loss, such as osteoporosis [7], but have also been shown to inhibit particle-induced osteolysis [39]. However, the long-term use of BPs and other pharmaceuticals often results in serious adverse effects, such as an increased risk of osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer [6]. Statins, a drug usually used to lower blood cholesterol levels and reduce the risk of symptoms related to atherosclerosis, targets the mevalonate pathway of osteoclasts, which affect the same inhibition mechanism as bisphosphonates. Statins have been shown to markedly reduce the severity of particle-induced osteolysis in a murine calvarial model [5]. However, as with BPs, the use of statins can present a number of side effects when used long-term, such as rhabdomyolysis, cognitive loss, neuropathy, hepatic dysfunction, and sexual dysfunction [8].

There is increasing interest in alternative methods such as traditional Chinese medicine for treating diseases as clinicians look to reduce long-term complications associated with conventional medicine. It has reported that postmenopausal Chinese women with greater fruit intake have a significantly higher BMD than comparable women with a lower fruit intake [40]. Flavonoids, found in a wide diversity of food derived from fruit, have been recognized as potential dietary components to promote bone health [41, 42]. Nam et al. also indicated that traditional mixed extracts of medicinal herbs can effectively inhibit the expression of inflammatory mediators in gouty arthritis on monosodium urate (MSU) crystals-induced gouty inflammation, demonstrating its potential for treating gouty arthritis [43]. Phytoestrogens, which are natural compounds that act to maintain healthy bones, have been shown to protect against postmenopausal bone loss [20]. This protective mechanism has been demonstrated with flavones [44, 45], flavanones [46, 47], flavonols [48], coumestans [49], and triterpenoids [46, 50]. Some phytoestrogens also have the ability to reduce osteolysis by blocking some modules in the RANKL signaling pathway, and subsequently reducing the release of cytokines [44, 45, 47, 51].

To our best knowledge, no studies to date have investigated whether WDL can reduce the risk of particle-induced osteolysis using an in-vivo murine calvarial model. The concentration of WDL used in this study was adopted from Tsai et al. [21] who showed that a low oral dose of WDL (4 mg/kg) administered for 4 weeks significantly suppressed the growth of prostate cancer cells. The results of our study showed that the BMD was significantly greater in the WDL 8w group (0.784 ± 0.014 mg/cc) than in the vehicle group (0.744 ± 0.032 mg/cc) (Fig. 2b). However, there was no significant difference between the WDL 4w and 8w groups in terms of the mean values of BV/TV and Tb.Th. On the other hand, the osteoclast numbers were significantly lower in the WDL 4w group (21.1 ± 9.8) and WDL 8w group (30.6 ± 4.0) than the vehicle group (44.1 ± 9.8) (Fig. 5).

Multinucleated giant cells are typically generated after implantation of medical advices, artificial joint or biomaterials, taking the form of foreign body giant cells. The formation of these giant cells is the end-stage of the inflammation or wound healing response [52]. Osteoclasts are specialized multinuclear giant cells derived from monocyte/macrophage lineage cells [53]. In this study, multinucleated giant cells were observed in the groups injected with polymer particles (Fig. 3). In addition, TRAP staining indicated that polymer particles were present in the periosteal cells and multinucleated giant cells in the mouse calvarial tissue (Fig. 4a, b).

Wear particles have been found in surrounding tissue after implantation of many different materials used in TJR, including ultra-high molecular weight polyethylene (UHMWPE) [54], poly(methyl methacrylate) (PMMA) [54], ceramics [54], metallic CoCrMo [55] and titanium alloy [55, 56]. Some studies used titanium particles to create particle-induced osteolysis animal models [44, 46, 53, 57, 58]. However, when used in joint replacements, titanium or its alloys generate fewer wear particles than polymers because of the relatively low mechanical strength of polymeric materials. In the authors’ previous animal studies, UHMWPE wear debris-induced animal models were developed to analyze the in vivo biological response to highly cross-linked and vitamin E-stabilized polyethylene [10] and to evaluate the potential role of strontium ranelate-contained medicine to treat osteolysis [11]. However, considerable time was spent preparing enough wear debris for these animal models, while polystyrene (PS) particles are readily available and are widely used both commercially and for biomedical research [59, 60]. PS particles have been used in many animal studies to create particle-induced osteolysis animal models [36,37,38]. Furthermore, given that the size distribution and shape of PS particles are easier to control, this study used PS particles for the animal model.

Previous studies treated murine calvarial osteolysis with bioactive compounds for 10–14 days after implantation of foreign particles [12, 44, 45, 47, 50, 61]. For instance, icariin, a bioactive flavonoid, has been proven to inhibit postmenopausal osteoporosis. Shao et al. gavage-fed mice with icariin at doses of 0.1 mg/g and 0.3 mg/g for 14 days to examine the effects on osteolysis in a particle-induced murine calvarial model. The results showed an increase in BMD and BV/TV over the control model, and the number of TRAP positive cells decreased [12]. Similarly, ursolic acid is an abundant triterpenoid present in over one hundred species of plants. It has been reported that ursolic acid isolated from loquat leaves can reduce bone loss in OVX mice [46]. Jiang et al. treated mice with 10 mg/kg and 40 mg/kg doses of ursolic acid administered through intraperitoneal injections for 14 days and found that ursolic acid protects against wear particle-induced osteolysis by suppressing osteoclast formation and function [50]. The treatment period in this current study, 4 weeks and 8 weeks, was longer than the referenced studies which only treated for a short-term of 2 weeks. No adverse effects were observed in this study after treating the mice for 8 weeks with WDL.

Bone remodeling is a dynamic equilibrium with molecular mechanisms, such as RANK/RANKL/OPG [62], NF-κB [63], and Wnt/BMP (bone morphogenic protein) [57, 64] signaling pathways playing critical roles in osteolysis. Although the trigger mechanisms for osteolysis are not yet fully understood, it is known that one of the mechanisms is the receptor activation of NF-κB ligand (RANKL) and osteoprotegerin (OPG) secreted from osteoblasts and osteogenic stromal cells, both of which act to maintain a balance between bone generation and resorption [62]. RANKL is required for the differentiation of osteoclast precursors into mature osteoclasts [58]. As the ratio of RANKL/OPG increases, the osteoclast precursors are easier influenced by RANKL signaling through the downstream activation of NF-κB/c-fos/NFATc1, subsequently causing the precursors to differentiate into mature osteoclasts. On the other hand, macrophages also plays a key role in wear particle-induced osteolysis [63, 65,66,67,68]. Cytokines (TNF-α and IL-1β, etc.) and other mediators of pro-inflammation from activated macrophages can regulate or stimulate other tissue-resident macrophages to promote osteoclastogenesis [66]. These cytokines also regulate JNK and the p38/ERK signaling pathway to induce NFATc1, one of the downstream factors in the RANKL signaling pathway, which can lead to osteolysis.

Studies have shown that some compounds from Chinese herbal medicines can treat particle-induced osteolysis by inhibiting the modules in the NF-κB signaling pathway, the main mechanism in the regulation of osteolysis, to effect the balance of osteoclasts and osteoblasts [12, 45, 50, 61, 68]. WDL is known for its ability to block the phosphorylation of IκBα, which acts to regulate the transcription of NF-κB mediated genes, inhibiting LPS-induced pro-inflammation [69]. Annie et al. demonstrated how an extract from Wedelia chinensis attenuated OVX-induced bone loss in mice [70]. WDL extracted from Ecliptae herba has been shown to inhibit osteoclastogenesis of RAW 264.7 cells treated with RANKL [35], and prevent OVX-induced bone loss by inhibiting osteoclast activity and enhancing osteoblast activity [34]. Furthermore, it has been confirmed that WDL can regulate the RANKL-related NF-κB/c-fos/NFATc1 pathway to suppress osteoclastogenesis [26, 71], and also regulate the Wnt/β-catenin signaling pathway to induce osteoblastogenesis [71, 72]. The authors concluded that oral WDL could improve bone formation and inhibit resorption by affecting the balance of osteoclasts and osteoblasts. However, the mechanism leading to the inhibition of osteolysis by WDL still needs to be determined.

Some limitations of this study should be mentioned. First, murine calvarial models allow for a low-cost study with relatively quick results, but the models use a flat bone instead of a long bone and the particles are injected on the cortical bone surface rather than into cancellous bone. Second, as detailed above, the WDL dose used in this study was adopted from other related publications. However, the most effective dose for treating osteolysis in vivo has yet to be determined and requires further study. Third, osteoclast numbers were counted through qualitative analysis, not quantitative analysis. When injected onto the calvaria, the particles randomly precipitated and then a section was chosen for histological staining. This sampling approach may not represent true osteoclast numbers. Further studies are recommended to investigate inflammatory makers. Accepting the above limitations, this animal study identified the potential role of wedelolactone for treating particle-induced osteolysis.

Conclusions

This study indicated that wedelolactone (WDL), a Chinese herbal medicine, could help to maintain bone quality. Oral WDL was shown to suppress osteoclast numbers and maintain the level of BMD over time in a particle-induced osteolysis murine clavarial model. Moving forward, WDL could be potentially developed as a functional food for lowering the risk of particle-induced osteolysis after total joint replacement.

Availability of data and materials

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

TJR:

Total Joint Replacement

WDL:

Wedelolactone

BMD:

Bone Mineral Density

BV/TV:

Bone Volume/Tissue Volume

Tb.Th:

Trabecular Thickness

ISO:

International Organization for Standardization

RANKL:

Receptor activator of nuclear factor kappa-Î’ ligand

OPG:

Osteoprotegerin

OVX:

Ovariectomy

References

  1. Sonntag R, Reinders J, Kretzer JP. What’s next? Alternative materials for articulation in total joint replacement. Acta Biomater. 2012;8(7):2434–41. https://doi.org/10.1016/j.actbio.2012.03.029.

    Article  CAS  PubMed  Google Scholar 

  2. Colston J, Atkins B. Bone and joint infection. Clin Med (Lond). 2018;18(2):150–4. https://doi.org/10.7861/clinmedicine.18-2-150.

    Article  Google Scholar 

  3. Ingham E, Fisher J. The role of macrophages in osteolysis of total joint replacement. Biomaterials. 2005;26(11):1271–86.

    Article  CAS  Google Scholar 

  4. Ren K, Dusad A, Zhang Y, Wang D. Therapeutic intervention for wear debris-induced aseptic implant loosening. Acta Pharm Sin B. 2013;3(2):76–85. https://doi.org/10.1016/j.apsb.2013.02.005.

    Article  Google Scholar 

  5. von Knoch F, Heckelei A, Wedemeyer C, Saxler G, Hilken G, Henschke F, et al. The effect of simvastatin on polyethylene particle-induced osteolysis. Biomaterials. 2005;26(17):3549–55. https://doi.org/10.1016/j.biomaterials.2004.09.043.

    Article  CAS  Google Scholar 

  6. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med. 2013;126(1):13–20. https://doi.org/10.1016/j.amjmed.2012.06.023.

    Article  CAS  PubMed  Google Scholar 

  7. Yamazaki T, Yamori M, Yamamoto K, Saito K, Asai K, Sumi E, et al. Risk of osteomyelitis of the jaw induced by oral bisphosphonates in patients taking medications for osteoporosis: a hospital-based cohort study in Japan. Bone. 2012;51(5):882–7. https://doi.org/10.1016/j.bone.2012.08.115.

    Article  CAS  PubMed  Google Scholar 

  8. Golomb BA, Evans MA. Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs. 2008;8(6):373–418. https://doi.org/10.2165/0129784-200808060-00004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012;11(6):933–46. https://doi.org/10.1080/14740338.2018.1394455.

    Article  CAS  PubMed  Google Scholar 

  10. Huang CH, Lu YC, Chang TK, Hsiao IL, Su YC, Yeh ST, et al. In vivo biological response to highly cross-linked and vitamin e-doped polyethylene—a particle-Induced osteolysis animal study. J Biomed Mater Res B Appl Biomater. 2016;104(3):561–7. https://doi.org/10.1002/jbm.b.33426.

    Article  CAS  PubMed  Google Scholar 

  11. Lu YC, Chang TK, Yeh ST, Fang HW, Lin CY, Hsu LI, et al. The potential role of strontium ranelate in treating particle-induced osteolysis. Acta Biomater. 2015;20:147–54. https://doi.org/10.1016/j.actbio.2015.03.034.

    Article  CAS  PubMed  Google Scholar 

  12. Shao H, Shen J, Wang M, Cui J, Wang Y, Zhu S, et al. Icariin protects against titanium particle-induced osteolysis and inflammatory response in a mouse calvarial model. Biomaterials. 2015;60:92–9. https://doi.org/10.1016/j.biomaterials.2015.04.048.

    Article  CAS  PubMed  Google Scholar 

  13. Millett PJ, Allen MJ, Bostrom MP. Effects of alendronate on particle-induced osteolysis in a rat model. J Bone Joint Surg Am. 2002;84-a(2):236–49. https://doi.org/10.2106/00004623-200202000-00011.

  14. Du Z, Zhu Z, Wang Y. The degree of peri-implant osteolysis induced by PEEK, CoCrMo, and HXLPE wear particles: a study based on a porous Ti6Al4V implant in a rabbit model. J Orthop Surg Res. 2018;13(1):23. https://doi.org/10.1186/s13018-018-0736-y.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Reginster JY, Neuprez A, Dardenne N, Beaudart C, Emonts P, Bruyere O. Efficacy and safety of currently marketed anti-osteoporosis medications. Best Pract Res Clin Endoc Metab. 2014;28(6):809–34. https://doi.org/10.1016/j.beem.2014.09.003.

    Article  CAS  Google Scholar 

  16. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporos Int. 2014;25(2):757–62. https://doi.org/10.1007/s00198-013-2469-4.

    Article  CAS  PubMed  Google Scholar 

  17. Cooper C, Fox KM, Borer JS. Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD. Osteoporos Int. 2014;25(2):737–45. https://doi.org/10.1007/s00198-013-2582-4.

    Article  CAS  PubMed  Google Scholar 

  18. Lam TP. Strengths and weaknesses of traditional Chinese medicine and Western medicine in the eyes of some Hong Kong Chinese. J Epidemiol Community Health. 2001;55(10):762–5. https://doi.org/10.1136/jech.55.10.762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu YQ, Wang YX, Shi NN, Han XJ, Lu AP. Current situation of International Organization for Standardization/Technical Committee 249 international standards of traditional Chinese medicine. Chin J Integr Med. 2017;23(5):376–80. https://doi.org/10.1007/s11655-015-2439-0.

    Article  CAS  PubMed  Google Scholar 

  20. Leung PC, Siu WS. Herbal treatment for osteoporosis: a current review. J Tradit Complement Med. 2013;3(2):82–7. https://doi.org/10.4103/2225-4110.110407.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tsai CH, Lin FM, Yang YC, Lee MT, Cha TL, Wu GJ, et al. Herbal extract of Wedelia chinensis attenuates androgen receptor activity and orthotopic growth of prostate cancer in nude mice. Clin Cancer Res. 2009;15(17):5435–44. https://doi.org/10.1158/1078-0432.CCR-09-0298.

    Article  CAS  PubMed  Google Scholar 

  22. Sarveswaran S, Gautam SC, Ghosh J. Wedelolactone, a medicinal plant-derived coumestan, induces caspase-dependent apoptosis in prostate cancer cells via downregulation of PKCε without inhibiting Akt. Int J Oncol. 2012;41(6):2191–9. https://doi.org/10.3892/ijo.2012.1664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang YT, Wen CC, Chen YH, Huang WC, Huang LT, Lin WC, et al. Dietary uptake of Wedelia chinensis extract attenuates dextran sulfate sodium-induced colitis in mice. PLoS ONE. 2013;8(5):e64152-e. https://doi.org/10.1371/journal.pone.0064152.

    Article  CAS  Google Scholar 

  24. Lin WC, Wen CC, Chen YH, Hsiao PW, Liao JW, Peng CI, et al. Integrative approach to analyze biodiversity and anti-inflammatory bioactivity of Wedelia medicinal plants. PLoS ONE. 2015;10(6):e0129067-e. https://doi.org/10.1371/journal.pone.0129067.

    Article  CAS  Google Scholar 

  25. Ding S, Hou X, Yuan J, Tan X, Chen J, Yang N, et al. Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-induced oxidant stress and inflammation responses through Nrf2 pathway. Int Immunopharmacol. 2015;29(2):648–55. https://doi.org/10.1016/j.intimp.2015.09.015.

    Article  CAS  PubMed  Google Scholar 

  26. Yuan F, Chen J, Sun PP, Guan S, Xu J. Wedelolactone inhibits LPS-induced pro-inflammation via NF-kappaB pathway in RAW 264.7 cells. J Biomed Sci. 2013;20:84. https://doi.org/10.1186/1423-0127-20-84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kobori M, Yang Z, Gong D, Heissmeyer V, Zhu H, Jung YK, et al. Wedelolactone suppresses LPS-induced caspase-11 expression by directly inhibiting the IKK complex. Cell Death Differ. 2004;11(1):123–30. https://doi.org/10.1038/sj.cdd.4401325.

    Article  CAS  PubMed  Google Scholar 

  28. Roy RK, Thakur M, Dixit VK. Hair growth promoting activity of Eclipta alba in male albino rats. Arch Dermatol Res. 2008;300(7):357–64. https://doi.org/10.1007/s00403-008-0860-3.

    Article  CAS  PubMed  Google Scholar 

  29. Lu Y, Hu D, Ma S, Zhao X, Wang S, Wei G, et al. Protective effect of wedelolactone against CCl4-induced acute liver injury in mice. Int Immunopharmacol. 2016;34:44–52. https://doi.org/10.1016/j.intimp.2016.02.003.

    Article  CAS  PubMed  Google Scholar 

  30. Luo Q, Ding J, Zhu L, Chen F, Xu L. Hepatoprotective Effect of Wedelolactone against Concanavalin A-Induced Liver Injury in Mice. Ame J Chin Med. 2018;46(4):819–33. https://doi.org/10.1142/S0192415X1850043X.

    Article  CAS  Google Scholar 

  31. Maya S, Prakash T, Goli D. Evaluation of neuroprotective effects of wedelolactone and gallic acid on aluminium-induced neurodegeneration: relevance to sporadic amyotrophic lateral sclerosis. Eur J Pharmacol. 2018;835:41–51. https://doi.org/10.1016/j.ejphar.2018.07.058.

    Article  CAS  PubMed  Google Scholar 

  32. Peng YG, Zhang L. Wedelolactone suppresses cell proliferation and migration through AKT and AMPK signaling in melanoma. J Dermatolog Treat. 2019;30(4):389–95. https://doi.org/10.1080/09546634.2018.1527996.

    Article  CAS  PubMed  Google Scholar 

  33. Nehybova T, Smarda J, Daniel L, Stiborek M, Kanicky V, Spasojevic I, et al. Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. Int J Mol Sci. 2017;18(4):729. https://doi.org/10.3390/ijms18040729.

    Article  CAS  PubMed Central  Google Scholar 

  34. Liu YQ, Hong ZL, Zhan LB, Chu HY, Zhang XZ, Li GH. Wedelolactone enhances osteoblastogenesis by regulating Wnt/beta-catenin signaling pathway but suppresses osteoclastogenesis by NF-kappaB/c-fos/NFATc1 pathway. Sci Rep. 2016;6:32260. https://doi.org/10.1038/srep32260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu YQ, Zhan LB, Liu T, Cheng MC, Liu XY, Xiao HB. Inhibitory effect of Ecliptae herba extract and its component wedelolactone on pre-osteoclastic proliferation and differentiation. J Ethnopharmacol. 2014;157:206–11. https://doi.org/10.1016/j.jep.2014.09.033.

    Article  CAS  PubMed  Google Scholar 

  36. Ma T, Ortiz SG, Huang Z, Ren P, Smith RL, Goodman SB. In vivo murine model of continuous intramedullary infusion of particles–a preliminary study. J Biomed Mater Res Part B Appl Biomater. 2009;88(1):250–3. https://doi.org/10.1002/jbm.b.31175.

    Article  CAS  Google Scholar 

  37. Ortiz SG, Ma T, Regula D, Smith RL, Goodman SB. Continuous intramedullary polymer particle infusion using a murine femoral explant model. J Biomed Mater Res B Appl Biomater. 2008;87(2):440–6. https://doi.org/10.1002/jbm.b.31122.

    Article  CAS  PubMed  Google Scholar 

  38. Chang TK, Lu YC, Yeh ST, Lin TC, Huang CH, Huang CH. In vitro and in vivo biological responses to graphene and graphene oxide: a murine calvarial animal study. Int J Nanomed. 2020;15:647–59. https://doi.org/10.2147/IJN.S231885.

    Article  CAS  Google Scholar 

  39. Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin Orthop Relat Res. 2007;454:251–61. https://doi.org/10.1097/01.blo.0000238813.95035.1b.

    Article  PubMed  Google Scholar 

  40. Chen YM, Ho SC, Woo JL. Greater fruit and vegetable intake is associated with increased bone mass among postmenopausal Chinese women. Br J Nutr. 2006;96(4):745–51.

    CAS  PubMed  Google Scholar 

  41. Weaver CM, Alekel DL, Ward WE, Ronis MJ. Flavonoid intake and bone health. J Nutr Gerontol Geriatr. 2012;31(3):239–53. https://doi.org/10.1080/21551197.2012.698220.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Welch AA, Hardcastle AC. The effects of flavonoids on bone. Curr Osteoporos Rep. 2014;12(2):205–10. https://doi.org/10.1007/s11914-014-0212-5. https://doi.org/10.1016/S1875-5364(17)30084-5.

  43. Nam JS, Jagga S, Sharma AR, Lee JH, Park JB, Jung JS, et al. Anti-inflammatory effects of traditional mixed extract of medicinal herbs (MEMH) on monosodium urate crystal-induced gouty arthritis. Chin J Nat Med. 2017;15(8):561–75. https://doi.org/10.1016/S1875-5364(17)30084-5.

    Article  CAS  PubMed  Google Scholar 

  44. Shin DK, Kim MH, Lee SH, Kim TH, Kim SY. Inhibitory effects of luteolin on titanium particle-induced osteolysis in a mouse model. Acta Biomater. 2012;8(9):3524–31. https://doi.org/10.1016/j.actbio.2012.05.002.

    Article  CAS  PubMed  Google Scholar 

  45. Zhao S, Sun Y, Li X, Wang J, Yan L, Zhang Z, et al. Scutellarin inhibits RANKL-mediated osteoclastogenesis and titanium particle-induced osteolysis via suppression of NF-kappaB and MAPK signaling pathway. Int Immunopharmacol. 2016;40:458–65. https://doi.org/10.1016/j.intimp.2016.09.031.

    Article  CAS  PubMed  Google Scholar 

  46. Wang W, Wu C, Tian B, Liu X, Zhai Z, Qu X, et al. The inhibition of RANKL-induced osteoclastogenesis through the suppression of p38 signaling pathway by naringenin and attenuation of titanium-particle-induced osteolysis. Int J Mol Sci. 2014;15(12):21913–34. https://doi.org/10.3390/ijms151221913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu X, Zhao X, Wu T, Zhou Z, Gao Y, Wang X, et al. Inhibiting wear particles-induced osteolysis with naringin. Int Orthop. 2013;37(1):137–43. https://doi.org/10.1007/s00264-012-1668-5.

    Article  PubMed  Google Scholar 

  48. Wang QS, Wang GF, Lu YR, Cui YL, Li H, Li RX, et al. The Combination of icariin and constrained dynamic loading stimulation attenuates bone loss in ovariectomy-induced osteoporotic mice. J Orthop Res. 2018;36(5):1415–24. https://doi.org/10.1002/jor.23777.

    Article  CAS  PubMed  Google Scholar 

  49. Zhai Y, Li Y, Wang Y, Cui J, Feng K, Kong X, et al. Psoralidin, a prenylated coumestan, as a novel anti-osteoporosis candidate to enhance bone formation of osteoblasts and decrease bone resorption of osteoclasts. Eur J Pharmacol. 2017;801:62–71. https://doi.org/10.1016/j.ejphar.2017.03.001.

    Article  CAS  PubMed  Google Scholar 

  50. Jiang C, Xiao F, Gu X, Zhai Z, Liu X, Wang W, et al. Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-kappaB signaling. Biochimie. 2015;111:107–18. https://doi.org/10.1016/j.biochi.2015.02.002.

    Article  CAS  PubMed  Google Scholar 

  51. Yang C, Liu W, Zhang X, Zeng B, Qian Y. Naringin increases osteoprotegerin expression in fibroblasts from periprosthetic membrane by the Wnt/β-catenin signaling pathway. J Orthop Surg Res. 2020;15(1):600. https://doi.org/10.1186/s13018-020-02145-z.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20(2):86–100. https://doi.org/10.1016/j.smim.2007.11.004.

    Article  CAS  PubMed  Google Scholar 

  53. Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, et al. Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. J Biol Chem. 2015;290(2):716–26. https://doi.org/10.1074/jbc.M114.568360.

    Article  CAS  PubMed  Google Scholar 

  54. Gibon E, Córdova LA, Lu L, Lin TH, Yao Z, Hamadouche M, et al. The biological response to orthopedic implants for joint replacement. II: polyethylene, ceramics, PMMA, and the foreign body reaction. J Biomed Mater Res B Appl Biomater. 2017;105(6):1685–91. https://doi.org/10.1002/jbm.b.33676.

    Article  CAS  PubMed  Google Scholar 

  55. Gibon E, Amanatullah DF, Loi F, Pajarinen J, Nabeshima A, Yao Z, et al. The biological response to orthopaedic implants for joint replacement: part I: metals. J Biomed Mater Res B Appl Biomater. 2017;105(7):2162–73. https://doi.org/10.1002/jbm.b.33734.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang L, Haddouti EM, Welle K, Burger C, Wirtz DC, Schildberg FA, et al. The effects of biomaterial implant wear debris on osteoblasts. Front Cell Dev Biol. 2020;8:352. https://doi.org/10.3389/fcell.2020.00352.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Nam JS, Sharma AR, Jagga S, Lee DH, Sharma G, Nguyen LT, et al. Suppression of osteogenic activity by regulation of WNT and BMP signaling during titanium particle induced osteolysis. J Biomed Mater Res A. 2017;105(3):912–26. https://doi.org/10.1002/jbm.a.36004.

    Article  CAS  PubMed  Google Scholar 

  58. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4(8):638–49. https://doi.org/10.1038/nrg1122.

    Article  CAS  PubMed  Google Scholar 

  59. Qiu J, Camargo PHC, Jeong U, Xia Y. Synthesis, transformation, and utilization of monodispersed colloidal spheres. Acc Chem Res. 2019;52(12):3475–87. https://doi.org/10.1021/acs.accounts.9b00490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li L, Sun S, Tan L, Wang Y, Wang L, Zhang Z, et al. Polystyrene nanoparticles reduced ROS and inhibited ferroptosis by triggering lysosome stress and TFEB nucleus translocation in a size-dependent manner. Nano Lett. 2019;19(11):7781–92. https://doi.org/10.1021/acs.nanolett.9b02795.

    Article  CAS  PubMed  Google Scholar 

  61. Jiao Z, Xu W, Zheng J, Shen P, Qin A, Zhang S, et al. Kaempferide prevents titanium particle induced osteolysis by suppressing JNK activation during osteoclast formation. Sci Rep. 2017;7(1):16665. https://doi.org/10.1038/s41598-017-16853-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9(Suppl 1):S1. https://doi.org/10.1186/ar2165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goodman SB, Gibon E, Pajarinen J, Lin TH, Keeney M, Ren PG, et al. Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. J R Soc Interface. 2014;11(93):20130962. https://doi.org/10.1098/rsif.2013.0962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jagga S, Sharma AR, Lee YH, Nam JS, Lee SS. Sclerostin-mediated impaired osteogenesis by fibroblast-like synoviocytes in the particle-induced osteolysis model. Front Mol Biosci. 2021;8: 666295. https://doi.org/10.3389/fmolb.2021.666295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lei P, Dai Z, Zhang YS, Liu H, Niu W, Li K, et al. Macrophage inhibits the osteogenesis of fibroblasts in ultrahigh molecular weight polyethylene (UHMWPE) wear particle-induced osteolysis. J Orthop Surg Res. 2019;14(1):80. https://doi.org/10.1186/s13018-019-1119-8.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Qiu J, Peng P, Xin M, Wen Z, Chen Z, Lin S, et al. ZBTB20-mediated titanium particle-induced peri-implant osteolysis by promoting macrophage inflammatory responses. Biomater Sci. 2020;8(11):3147–63. https://doi.org/10.1039/d0bm00147c.

    Article  CAS  PubMed  Google Scholar 

  67. Lin S, Wen Z, Li S, Chen Z, Li C, Ouyang Z, et al. LncRNA Neat1 promotes the macrophage inflammatory response and acts as a therapeutic target in titanium particle-induced osteolysis. Acta Biomater. 2022;142:345–60. https://doi.org/10.1016/j.actbio.2022.02.007.

    Article  CAS  PubMed  Google Scholar 

  68. Guangtao F, Zhenkang W, Zhantao D, Mengyuan L, Qingtian L, Yuanchen M, et al. Icariin alleviates wear particle-induced periprosthetic osteolysis via down-regulation of the estrogen receptor α-mediated NF-κB signaling pathway in macrophages. Front Pharmacol. 2021;12:746391. https://doi.org/10.3389/fphar.2021.746391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shen P, Yang X, Jiang J, Wang X, Liang T, He L. Wedelolactone from Eclipta alba inhibits lipopolysaccharide-enhanced cell proliferation of human renal mesangial cells via NF-kappaB signaling pathway. Am J Transl Res. 2017;9(5):2132–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Annie S, Prabhu RG, Malini S. Activity of Wedelia calendulacea Less in post-menopausal osteoporosis. Phytomedicine. 2006;13(1–2):43–8. https://doi.org/10.1016/j.phymed.2004.01.011.

    Article  CAS  PubMed  Google Scholar 

  71. Deng X, Liang LN, Zhu D, Zheng LP, Yu JH, Meng XL, et al. Wedelolactone inhibits osteoclastogenesis but enhances osteoblastogenesis through altering different semaphorins production. Int Immunopharmacol. 2018;60:41–9. https://doi.org/10.1016/j.intimp.2018.04.037.

    Article  CAS  PubMed  Google Scholar 

  72. Zhu D, Deng X, Han XF, Sun XX, Pan TW, Zheng LP, et al. Wedelolactone enhances osteoblastogenesis through ERK- and JNK-mediated BMP2 expression and Smad/1/5/8 phosphorylation. Molecules. 2018;23(3):561. https://doi.org/10.3390/molecules23030561.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are pleased to acknowledge the financial support of Mackay Memorial Hospital (MMH). We acknowledge experimental support from the Electron Microscope Laboratory of MMH. We also thank the Taiwan Animal Consortium (MOST 107-2319-B-001-002) Taiwan Mouse Clinic and Tron Medicalbio Corp for technical support in the micro-CT experiments. The authors particularly thank Colin J. McClean for his kind assistance in language editing and proofreading of this manuscript.

Funding

The financial support of Mackay Memorial Hospital (MMH-106-145) and the Taiwan Animal Consortium Taiwan Mouse Clinic (MOST 107-2319-B-001-002) for the micro-CT experiments.

Author information

Authors and Affiliations

  1. Department of Medicine, MacKay Medical College, New Taipei City, Taiwan

    Yung-Chang Lu, Ting-Kuo Chang & Chun-Hsiung Huang

  2. Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan

    Yung-Chang Lu, Ting-Kuo Chang, Tzu-Chiao Lin, Shu-Ting Yeh, Chun-Hsiung Huang & Chang-Hung Huang

  3. Department of Orthopaedic Surgery, MacKay Memorial Hospital, Taipei, Taiwan

    Yung-Chang Lu, Ting-Kuo Chang, Chun-Hsiung Huang & Chang-Hung Huang

  4. Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan

    Hsu-Wei Fang

  5. Department of Orthopaedic Surgery, Changhua Christian Hospital, Changhua, Taiwan

    Chun-Hsiung Huang

  6. School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chang-Hung Huang

  7. Institute of Geriatric Welfare Technology and Science, MacKay Medical College, New Taipei City, Taiwan

    Chang-Hung Huang

Authors
  1. Yung-Chang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting-Kuo Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tzu-Chiao Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shu-Ting Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hsu-Wei Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chun-Hsiung Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chang-Hung Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y-CL: conceptualization and methodology. T-KC: methodology and data description. T-CL: animal study, data analysis, and writing. S-TY: investigation and data analysis. C-HH: supervision, review and editing. C-HH: supervision, conceptualization, writing, review and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chang-Hung Huang.

Ethics declarations

Ethics approval and consent to participate

(1) This material has not been published in whole or in part elsewhere; (2) the manuscript is not currently being considered for publication in another journal; (3) all authors have been personally and actively involved in substantive work leading to the manuscript, and will hold themselves jointly and individually responsible for its content. (4)The animal protocol use in this study was approved by the Institutional Animal Care and Use Committee, where the study was performed.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lu, YC., Chang, TK., Lin, TC. et al. The potential role of herbal extract Wedelolactone for treating particle-induced osteolysis: an in vivo study. J Orthop Surg Res 17, 335 (2022). https://doi.org/10.1186/s13018-022-03228-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13018-022-03228-9

Keywords

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X