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It has been known that periodontal ligament‐associated protein‐1 (PLAP‐1/Asporin) not only inhibits cartilage formation in osteoarthritis, but it also influences the healing of skull defect. However, the effect and mechanism of PLAP‐1/Asporin on the mutual regulation of osteoclasts and osteoblasts in periodontitis are not clear. In this study, we utilized a PLAP‐1/Asporin gene knockout (KO) mouse model to research this unknown issue. We cultured mouse bone marrow mesenchymal stem cells with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) for osteogenic induction in vitro. The molecular mechanism of PLAP‐1/Asporin in the regulation of osteoblasts was detected by immunoprecipitation, immunofluorescence, and inhibitors of signaling pathways. The results showed that the KO of PLAP‐1/Asporin promoted osteogenic differentiation through transforming growth factor beta 1 (TGF‐β1)/Smad3 in inflammatory environments. We further found the KO of PLAP‐1/Asporin inhibited osteoclast differentiation and promoted osteogenic differentiation through the TGF‐β1/Smad signaling pathway in an inflammatory coculture system. The experimental periodontitis model was established by silk ligation and the alveolar bone formation in PLAP‐1/Asporin KO mice was promoted through TGF‐β1/Smad3 signaling pathway. The subcutaneous osteogenesis model in nude mice also confirmed that the KO of PLAP‐1/Asporin promoted bone formation by the histochemical staining. In conclusion, PLAP‐1/Asporin regulated the differentiation of osteoclasts and osteoblasts through TGF‐β1/Smad signaling pathway. The results of this study lay a theoretical foundation for the further study of the pathological mechanism underlying alveolar bone resorption, and the prevention and treatment of periodontitis. [ABSTRACT FROM AUTHOR]

Bone resorption can be caused by excessive differentiation and/or activation of bone‐resorbing osteoclasts. While microbe‐associated molecular patterns can influence the differentiation and activation of bone cells, little is known about the role of lipoteichoic acid (LTA), a major cell wall component of Gram‐positive bacteria, in the regulation of bone metabolism. In this study, we investigated the effect of LTA on bone metabolism using wild‐type Staphylococcus aureus and the LTA‐deficient mutant strain. LTA‐deficient S. aureus induced higher bone loss and osteoclast differentiation than wild‐type S. aureus. LTA isolated from S. aureus (SaLTA) inhibited osteoclast differentiation from committed osteoclast precursors in the presence of various osteoclastogenic factors by downregulating the expression of NFATc1. Remarkably, SaLTA attenuated the osteoclast differentiation from committed osteoclast precursors of TLR2−/− or MyD88−/− mice and from the committed osteoclast precursors transfected with paired immunoglobulin‐like receptor B‐targeting siRNA. SaLTA directly interacted with gelsolin, interrupting the gelsolin‐actin dissociation which is a critical process for osteoclastogenesis. Moreover, SaLTA suppressed the mRNA expression of dendritic cell‐specific transmembrane protein, ATPase H+ transporting V0 subunit D2, and Integrin, which encode proteins involved in cell‐cell fusion of osteoclasts. Notably, LTAs purified from probiotics, including Bacillus subtilis, Enterococcus faecalis, and Lactobacillus species, also suppressed Pam2CSK4‐ or RANKL‐induced osteoclast differentiation. Taken together, these results suggest that LTAs have anti‐resorptive activity through the inhibition of osteoclastogenesis by interfering with the gelsolin‐actin dissociation and may be used as effective therapeutic agents for the prevention or treatment of inflammatory bone diseases. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein (BMP) signaling is well known in bone homeostasis. However, the physiological effects of BMP signaling on mandibles are largely unknown, as the mandible has distinct functions and characteristics from other bones. In this study, we investigated the roles of BMP signaling in bone homeostasis of the mandibles by deleting BMP type I receptor Acvr1 in osteoblast lineage cells with Osterix‐Cre. We found mandibular bone loss in conditional knockout mice at the ages of postnatal day 21 and 42 in an age‐dependent manner. The decreased bone mass was related to compromised osteoblast differentiation together with enhanced osteoclastogenesis, which was secondary to the changes in osteoblasts in vivo. In vitro study revealed that deletion of Acvr1 in the mandibular bone marrow stromal cells (BMSCs) significantly compromised osteoblast differentiation. When wild type bone marrow macrophages were cocultured with BMSCs lacking Acvr1 both directly and indirectly, both proliferation and differentiation of osteoclasts were induced as evidenced by an increase of multinucleated cells, compared with cocultured with control BMSCs. Furthermore, we demonstrated that the increased osteoclastogenesis in vitro was at least partially due to the secretion of soluble receptor activator of nuclear factor‐κB ligand (sRANKL), which is probably the reason for the mandibular bone loss in vivo. Overall, our results proposed that ACVR1 played essential roles in maintaining mandibular bone homeostasis through osteoblast differentiation and osteoblast‐osteoclast communication via sRANKL. [ABSTRACT FROM AUTHOR]

Considering the high rate of osteoclast‐related diseases worldwide, research targeting osteoclast formation/function is crucial. In vitro, we demonstrated that chitooligosaccharide (CS) dramatically inhibited osteoclastogenesis as well as osteoclast function dose‐dependently. CS suppressed osteoclast‐specific genes expression during osteoclastogenesis. Furthermore, we found that CS attenuated receptor activator of nuclear factor kappa B ligand (RANKL)‐mediated mitogen‐activated protein kinase (MAPK) pathway involving p38, erk1/2, and jnk, leading to the reduced expression of c‐fos and nuclear factor of activated T cells c1 (NFATc1) during osteoclast differentiation. In vivo, we found CS protected rats from periodontitis‐induced alveolar bone loss by micro‐computerized tomography and histological analysis. Overall, CS inhibited RANKL‐induced osteoclastogenesis and ligature‐induced rat periodontitis model, probably by suppressing the MAPK/c‐fos/NFATc1 signaling pathway. Therefore, CS may be a safe and promising treatment for osteoclast‐related diseases. [ABSTRACT FROM AUTHOR]

Bone‐resorbing osteoclasts are differentiated from macrophages (MΦ) by M‐CSF and RANKL. MΦ can be mainly classified into M1 and M2 MΦ, which are proinflammatory and anti‐inflammatory, respectively, but little is known about their osteoclastogenic potential. Here, we investigated the osteoclastogenic potential of MΦ subtypes. When the two MΦ subtypes were differentiated into osteoclasts using M‐CSF and RANKL, M2 MΦ more potently differentiated into osteoclasts than M1 MΦ. M2 MΦ generated with IL‐4 or IL‐10 also showed enhanced osteoclast differentiation compared with M1 MΦ induced by IFN‐γ and lipopolysaccharide. In addition, robust bone‐resorptive capacity and giant actin rings, which are features of mature osteoclasts, were observed in M2, but not M1 MΦ, under the osteoclast differentiation condition. Osteoclast differentiation was significantly increased in CD206+ M2 MΦ but not in CD86+ M1 MΦ. Compared with M1 MΦ, c‐Fms and RANK were highly expressed in M2 MΦ. Enhanced osteoclastogenesis of M2 MΦ was mediated through sustained ERK activation, followed by efficient c‐Fos and NFATc1 induction. Notably, the osteoclastogenic potential of M1 MΦ converted into M2 MΦ by exposure to M‐CSF was higher than that of M2 MΦ converted into M1 MΦ by exposure to GM‐CSF. Silencing IRF5, which is responsible for M1 MΦ polarization, increased osteoclast differentiation by enhancing c‐Fms expression and activation of ERK, c‐Fos, CREB, and NFATc1, which was inhibited by overexpression of IRF5. Collectively, M2 MΦ are suggested to be more efficient osteoclast precursors than M1 MΦ because of the attenuated expression of IRF5. [ABSTRACT FROM AUTHOR]

Osteoporosis is a class of metabolic bone disease caused by complexed ramifications. Overactivation of osteoclasts due to a sudden decreased estrogen level plays a pivotal role for postmenopausal women suffering from osteoporosis. Therefore, inhibiting osteoclast formation and function has become a major direction for the treatment of osteoporosis. Tiliroside (Tle) is a salutary dietary glycosidic flavonoid extracted from Oriental Paperbush flower, which has been reported to have an anti‐inflammation effect. However, whether Tle affects the osteoclastogenesis and bone resorption remains unknown. Herein, we demonstrate that Tle prevents bone loss in ovariectomy in mice and inhibits osteoclast differentiation and bone resorption stimulated by receptor activator of nuclear factor‐κB ligand (RANKL) in vitro. Molecular mechanism studies reveal that Tle reduces RANKL‐induced activation of mitogen‐activated protein kinase and T‐cell nuclear factor 1 pathways, and osteoclastogenesis‐related marker gene expression, including cathepsin K (Ctsk), matrix metalloproteinase 9, tartrate‐resistant acid phosphatase (Acp5), and Atp6v0d2. Our research indicates that Tle suppresses osteoclastogenesis and bone loss by downregulating the RANKL‐mediated signaling protein activation and expression. In addition, Tle inhibits intracellular reactive oxygen species generation which is related to the formation of osteoclasts. Therefore, Tle might serve as a potential drug for osteolytic disease such as osteoporosis. [ABSTRACT FROM AUTHOR]

G protein‐coupled receptor 119 (GPR119) is known to be a promising therapeutic target for type 2 diabetes. Recently, it has been reported that the GPR119 agonist increases bone mineral density in an animal model of diabetes, suggesting that GPR119 may play a key role in bone metabolism. In this study, we investigated the functional role of GPR119 in receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast formation. We found that the GPR119 expression was markedly increased in preosteoclasts and then downregulated in mature osteoclasts. Activation of GPR119 with AS1269574, a potent selective agonist for GPR119, inhibited the generation of multinuclear osteoclasts from bone marrow‐derived macrophages. Confirming this observation, targeted silencing of GPR119 using short hairpin RNA abrogated the AS1269574‐mediated suppressive effect on osteoclast formation. GPR119 activation attenuated the expression of c‐Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and blocked RANKL‐stimulated phosphorylation of IκBα, c‐Jun N‐terminal protein kinase (JNK), and extracellular signal‐regulated kinase (ERK) but not p38. In addition, GPR119 activation suppressed preosteoclast fusion by downregulating the expression of the dendritic cell‐specific transmembrane (DC‐STAMP), a molecule that is essential for cell–cell fusion in osteoclast formation. Furthermore, ectopic expression of DC‐STAMP restored AS1269574‐mediated inhibition of osteoclast fusion. Taken together, our findings demonstrate that GPR119 plays a negative role in osteoclast differentiation and fusion induced by RANKL, and therefore may represent a potential target for bone resorption‐associated diseases. G protein‐coupled receptor 119 (GPR119) activation inhibits osteoclastogenesis and fusion induced by receptor activator of nuclear factor‐κB ligand (RANKL). GPR119 may become a new target for the treatment of bone‐erosive diseases characterized by increased osteoclast number. [ABSTRACT FROM AUTHOR]

Excessive osteoclast formation is one of the important pathological features of inflammatory bone destruction. Interleukin‐37 (IL‐37) is an anti‐inflammatory agent that is present throughout the body, but it displays low physiological retention. In our study, high levels of the IL‐37 protein were detected in clinical specimens from patients with bone infections. However, the impact of IL‐37 on osteoclast formation remains unclear. Next, IL‐37 alleviated the inflammatory bone destruction in the mouse in vivo. We used receptor activator of nuclear factor‐κB ligand and lipopolysaccharide to trigger osteoclastogenesis under physiological and pathological conditions to observe the role of IL‐37 in this process and explore the potential mechanism of this phenomenon. In both induction models, IL‐37 exerted inhibitory effects on osteoclast differentiation and bone resorption. Furthermore, IL‐37 decreased the phosphorylation of inhibitor of κBα and p65 and the expression of nuclear factor of activated T cells c1, while the dimerization inhibitor of myeloid differentiation factor 88 reversed the effects. These data provide evidence that IL‐37 modulates osteoclastogenesis and a theoretical basis for the clinical application of IL‐37 as a treatment for bone loss–related diseases. Interleukin 37 downregulates osteoclastogenesis through direct and indirect actions [ABSTRACT FROM AUTHOR]