The role of YAP/TAZ on joint and arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."

The emerging role of the semaphorin family in cartilage and osteoarthritis.

In the pathogenesis of osteoarthritis, various signaling pathways may influence the bone joint through a common terminal pathway, thereby contributing to the pathological remodeling of the joint. Semaphorins (SEMAs) are cell-surface proteins actively involved in and primarily responsible for regulating chondrocyte function in the pathophysiological process of osteoarthritis (OA). The significance of the SEMA family in OA is increasingly acknowledged as pivotal. This review aims to summarize the mechanisms through which different members of the SEMA family impact various structures within joints. The findings indicate that SEMA3A and SEMA4D are particularly relevant to OA, as they participate in cartilage injury, subchondral bone remodeling, or synovitis. Additionally, other elements such as SEMA4A and SEMA5A may also contribute to the onset and progression of OA by affecting different components of the bone and joint. The mentioned mechanisms demonstrate the indispensable role of SEMA family members in OA, although the detailed mechanisms still require further exploration.

The role of WWP1 and WWP2 in bone/cartilage development and diseases.

Bone and cartilage diseases are often associated with trauma and senescence, manifested as pain and limited mobility. The repair of bone and cartilage lesion by mesenchymal stem cells is regulated by various transcription factors. WW domain-containing protein 1 (WWP1) and WW domain-containing protein 2 (WWP2) are named for WW domain which recognizes PPXY (phono Ser Pro and Pro Arg) motifs of substrate. WWP1and WWP2 are prominent components of the homologous to the E6-AP carboxyl terminus (HECT) subfamily, a group of the ubiquitin ligase. Recently, some studies have found that WWP1 and WWP2 play an important role in the pathogenesis of bone and cartilage diseases and regulate the level and the transactivation of various transcription factors through ubiquitination. Therefore, this review summarizes the distribution and effects of WWP1 and WWP2 in the development of bone and cartilage, discusses the potential mechanism and therapeutic drugs in bone and cartilage diseases such as osteoarthritis, fracture, and osteoporosis.

Cyclic di-adenosine monophosphate regulates the osteogenic and adipogenic differentiation of hPDLSCs via MAPK and NF-κB signaling.

Cyclic di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that can be recognized by infected host cells and activate the immunoinflammatory response. The purpose of this study is to demonstrate the effect of c-di-AMP on the differentiation of human periodontal ligament stem cells (hPDLSCs) and its underlying mechanisms. In the present study, we find that the gingival crevicular fluid (GCF) of patients with chronic periodontitis has a higher expression level of c-di-AMP than that of healthy people. In vitro, c-di-AMP influences the differentiation of hPDLSCs by upregulating Toll-like receptors (TLRs); specifically, it inhibits osteogenic differentiation by activating NF-κB and ERK/MAPK and promotes adipogenic differentiation through the NF-κB and p38/MAPK signaling pathways. Inhibitors of TLRs or activated pathways reduce the changes induced by c-di-AMP. Our results establish the potential correlation among bacterial c-di-AMP, periodontal tissue homeostasis and chronic periodontitis pathogenesis.

Cellular communication network factor 1 interlinks autophagy and ERK signaling to promote osteogenesis of periodontal ligament stem cells.

OBJECTIVES: To investigate the effects of cellular communication network factor 1 (CCN1), a critical matricellular protein, on alveolar bone regeneration, and to elucidate the underlying molecular mechanism. BACKGROUND: In the process of orthodontic tooth movement, bone deposition on the tension side of human periodontal ligament stem cells (hPDLSCs) ensured high efficiency and long-term stability of the treatment. The matricellular protein CCN1 is responsive to mechanical stimulation, exhibiting important tasks in bone homoeostasis. However, the role and mechanism of CCN1 on alveolar bone remodeling of hPDLSCs remains unclear. METHODS: The expression and distribution of CCN1 in rat periodontal ligament were detected by immunofluorescence staining and immunohistochemical staining. ELISA verified the secretion of CCN1 triggered by stretch loading. To examine the mineralization ability of hPDLSCs induced by CCN1, Western blotting, qRT-PCR, ARS, and ALP staining were performed. CCK-8 and cell migration assay were performed to detect the cell proliferation rate and the wound healing. PI3K/Akt, MAPK, and autophagy activation were examined via Western blotting and immunofluorescence. RESULTS: Mechanical stimuli induced the release of CCN1 into extracellular environment by hPDLSCs. Knockdown of CCN1 attenuated the osteogenesis of hPDLSCs while rhCCN1 enhanced the expression of Runx2, Col 1, ALPL, and promoted the mineralization nodule formation. CCN1 activated PI3K/Akt and ERK signaling, and blockage of PI3K/Akt signaling reversed the accelerated cell migration triggered by CCN1. The enhanced osteogenesis induced by CCN1 was abolished by ERK signaling inhibitor PD98059 or autophagy inhibitor 3-MA. Further investigation demonstrated PD98059 abrogated the activation of autophagy. CONCLUSION: This study demonstrated that CCN1 promotes osteogenesis in hPDLSCs via autophagy and MAPK/ERK pathway.

Long noncoding RNA expression profiles in intermittent parathyroid hormone induced cementogenesis.

The aim of this study was to explore the involvement of long noncoding RNAs (lncRNAs) during intermittent parathyroid hormone (PTH) induced cementogenesis. Expression profiles of lncRNAs and mRNAs were obtained using high-throughput microarray. Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and coding-noncoding gene coexpression networks construction were performed. We identified 190 lncRNAs and 135 mRNAs that were differentially expressed during intermittent PTH-induced cementogenesis. In this process, the Wnt signaling pathway was negatively regulated, and eight lncRNAs were identified as possible core regulators of Wnt signaling. Based on the results of microarrray analysis, we further verified the repressed expression of Wnt signaling crucial components ß-catenin, APC and Axin2. Above all, we speculated that lncRNAs may play important roles in PTH-induced cementogenesis via the negative regulation of Wnt pathway.

Relative effectiveness of facemask therapy with alternate maxillary expansion and constriction in the early treatment of Class III malocclusion.

INTRODUCTION: This study aimed to investigate the relative efficacy of maxillary protraction combined with a modified alternate rapid maxillary expansion and constriction (Alt-RAMEC) protocol compared with conventional protocols in the early orthopedic treatment of skeletal Class III malocclusion. METHODS: A sample of 39 patients was divided into 3 groups on the basis of different interventions. Conventional facemask (FM) with splint-type intraoral devices was performed in the FM group (7 males and 5 females; mean age, 9.53 ± 1.37 years). Maxillary expansion with an activation rate of 0.5 mm/d (twice a day) followed by FM therapy was applied in the rapid maxillary expansion group (RME/FM) (6 males and 6 females; mean age, 9.31 ± 1.60 years). In the Alt-RAMEC/FM group (7 males and 8 females; mean age, 10.01 ± 1.31 years), Alt-RAMEC was started simultaneously and throughout the entire course of maxillary protraction, with repetitive alternations between activation and deactivation of expanders (0.5 mm/d for 7 days). The patients in all groups were instructed to wear FMs for a minimum of 12 h/d. Pretreatment and posttreatment lateral cephalograms were all traced and measured. RESULTS: The Alt-RAMEC group showed statistically more significant maxillary advancement than other groups (A-VRP, 3.87 mm vs 3.04 mm [RME/FM], vs 2.04 mm [FM]; P <0.05). Analysis of variance did not reveal significant intergroup differences in palatal plane angulation changes (P >0.05). No pronounced mandibular clockwise rotations were noted in the Alt-RAMEC/FM group with distinct intergroup differences (P <0.05). There were more skeletal effects (88.7%) during overjet correction in the Alt-RAMEC/FM protocol. CONCLUSIONS: A combination of the modified Alt-RAMEC protocol with FM revealed more favorable skeletal effects compared with FM and RME/FM protocols in treating prepubertal patients with maxillary deficiency.

The role of EphB4/ephrinB2 signaling in root repair after orthodontically-induced root resorption.

INTRODUCTION: This study aimed to investigate the effect of EphB4/ephrinB2 signaling on orthodontically-induced root resorption repair and the possible molecular mechanism behind it. METHODS: Seventy-two 6-week-old male Wistar rats were randomly divided into 3 groups: blank control group, physiological regeneration group (PHY), and EphB4 inhibitor local injection group (INH). A root repair model was built on experimental rats of the PHY and INH groups. The animals in the INH groups received a daily periodontal local injection of EphB4 inhibitor NVP-BHG712, whereas the blank control group and PHY groups received only the vehicle. RESULTS: Histologic staining and microcomputed tomography analysis showed that root regeneration was inhibited in the INH group compared with the PHY group with a greater number of osteoclasts. Immunohistochemical staining showed active EphB4/ephrinB2 signaling activities during root regeneration. The cementogenesis-related factors cementum attachment protein, alkaline phosphatase, osteopontin, and runt-related transcription factor 2, and osteoclastic-related factors RANKL and osteoprotegerin were affected by regulated EphB4/ephrinB2 signaling. CONCLUSIONS: These findings demonstrated that the EphB4/ephrinB2 signaling might be a promising therapeutic target for novel therapeutic approaches to reduce orthodontically-induced root resorption through enhancement of cementogenesis.

AFF4 enhances odontogenic differentiation of human dental pulp cells.

AFF4 is a component of super elongation complex (SECs) and functions as a scaffold protein to bridge the transcription elongation factors. It is associated with leukemia, HIV transcription, and head neck cancer. However, its role in odontogenic differentiation of dental pulp cells (DPCs) is unclear. Here, we show the expression of AFF4 is increased during odontogenesis. Depletion of AFF4 in human DPCs leads to a decrease of alkaline phosphatase (ALP) activity, calcium mineralization and odontogenic-related genes expression. On the contrary, Lentivirus-mediated overexpression of AFF4 induces the odontogenic potential of DPCs. Mechanistically, we found AFF4 regulates the transcription of NFIC, a key factor for tooth root formation. Overexpression of NFIC successfully rescues the restricted differentiation of AFF4-depleted cells. Our data demonstrate that AFF4 serves as a previously unknown regulator of odontogenesis.

A Bayesian network meta-analysis of orthopaedic treatment in Class III malocclusion: Maxillary protraction with skeletal anchorage or a rapid maxillary expander.

To evaluate and compare the effectiveness of orthopaedic treatment for Class III malocclusions using skeletal anchorage or a rapid maxillary expander for maxillary protraction. Electronic databases, including PubMed, EMBASE, Cochrane Library and Web of Science, were searched for randomized controlled trials (RCTs) and non-randomized clinical trials (CCTs) for orthopaedic treatment of Class III malocclusions. Five interventions were studied: a facemask with a maxillary temporary anchorage device (MTAD), a bone-anchored rapid maxillary expansion (BARME), a rapid maxillary expansion (RME), an alternate rapid maxillary expansion and contraction (Alt-RAMEC), and a bone-anchored intermaxillary traction (BAIMT). Eight outcomes (SNA, SNB, ANB, overjet, SN-GoGn, ANS-Me, IMPA (L1-MP), and U1-PP) were statistically polled. We conducted network meta-analysis using R statistical software with the GeMTC package. Twenty-five studies met the inclusion criteria. Compared with the RME group, the Alt-RAMEC group (mean difference (MD): 1.3; 95% credibility interval (CrI): 0.26, 2.3) and MTAD group (MD: 0.85; 95% CrI: 0.065, 1.6) showed a better effect on ANB in CCTs. Regarding the vertical relationship, the BAIMT group (MD: -2.2; 95% CrI: -5.2, 0.73) showed a smaller effect regarding increasing the vertical dimension of ANS-Me. The RME, MTAD and Alt-RAMEC group showed a higher ability to decrease the angle of L1-MP. The Alt-RAMEC and MTAD protocol have a higher possibility to obtain a skeletal and tooth effect in sagittal relationships. The BAIMT protocol can acquire a better skeletal effect in sagittal relationships with less vertical and dental changes. More well-designed RCTs are needed to ensure that the conclusion is reliable.

[The Study of Signal Pathway Regulating the Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells].

Osteogenesis of mesenchymal stem cells to differentiate between bone marrow by multiple signaling pathways that control, directly or indirectly affect small related transcription factor 2 (runt-related transcription factor 2, Runx2) and osteoblast specific transcription factor (osterix, Osx), the expression of osteogenesis key transcription factors, such as in the development and regeneration of the bone, bone repair has played a key role in the process of reconstruction. These pathways play their mechanism of action, but also intertwined associated constitute a complex signal transduction network, but due to the limitations of research methods, the osteogenic differentiation related signaling pathways of the specific mechanism is still unclear, if you can clarify these different signaling pathways play to the role of their relevant mechanism and the relationship between various pathways and the mechanism study of osteogenesis differentiation is of great importance. This article will review the progress of various signaling pathways in the regulation of osteogenic differentiation of bone marrow mesenchymal stem cells.

The role of neuropilin in bone/cartilage diseases.

Bone remodeling is the balance between osteoblasts and osteoclasts. Bone diseases such as osteoporosis and osteoarthritis are associated with imbalanced bone remodeling. Skeletal injury leads to limited motor function and pain. Neurophilin was initially identified in axons, and its various ligands and roles in bone remodeling, angiogenesis, neuropathic pain and immune regulation were later discovered. Neurophilin promotes osteoblast mineralization and inhibits osteoclast differentiation and its function. Neuropolin-1 provides channels for immune cell chemotaxis and cytokine diffusion and leads to pain. Neuropolin-1 regulates the proportion of T helper type 17 (Th17) and regulatory T cells (Treg cells), and affects bone immunity. Vascular endothelial growth factors (VEGF) combine with neuropilin and promote angiogenesis. Class 3 semaphorins (Sema3a) compete with VEGF to bind neuropilin, which reduces angiogenesis and rejects sympathetic nerves. This review elaborates on the structure and general physiological functions of neuropilin and summarizes the role of neuropilin and its ligands in bone and cartilage diseases. Finally, treatment strategies and future research directions based on neuropilin are proposed.

AFF4 regulates osteogenic potential of human periodontal ligament stem cells via mTOR-ULK1-autophagy axis.

Scaffold protein AF4/FMR2 family member 4 (AFF4) has been found to play a role in osteogenic commitment of stem cells. However, function of AFF4 in human periodontal ligament stem cells (hPDLSCs) has not been studied yet. This present study aims to investigate the biological effect of AFF4 on osteogenic differentiation of hPDLSCs and potential mechanistic pathway. First, AFF4 expression profile was evaluated in conditions of periodontitis and osteogenic differentiation of hPDLSCs by immunohistochemical staining, western blot and qRT-PCR. Next, si-RNA mediated knockdown and lentiviral transduction mediated overexpression of AFF4 were adopted to explore impact of AFF4 on osteogenic capacity of hPDLSCs. Then, possible mechanistic pathway was identified. At last, pharmacological agonist of autophagy, rapamycin, was utilized to affirm the role of autophagy in AFF4-regulated osteogenesis of hPDLSCs. First, AFF4 expressions were significantly lower in inflamed periodontal tissues and lipopolysaccharides-treated hPDLSCs than controls, and were up-regulated during osteogenic differentiation of hPDLSCs. Next, osteogenic potential of hPDLSCs was impaired by AFF4 knockdown and potentiated by AFF4 overexpression. Moreover, AFF4 was found to positively regulate autophagic activity in hPDLSCs. At last, rapamycin treatment was shown to be able to partly restore AFF4 knockdown-suppressed osteogenic differentiation. Our study demonstrates that AFF4 regulates osteogenic potential of hPDLSCs via targeting autophagic activity. The involvement of AFF4 in periodontal homeostasis was identified for the first time.

Long non-coding RNA LncTUG1 regulates favourable compression force-induced cementocytes mineralization via PU.1/TLR4/SphK1 signalling.

Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.

Loss of PA28γ exacerbates imbalanced differentiation of bone marrow stromal cells during bone formation and bone healing in mice.

Proteasome activator subunit 3 (PA28γ) is a member of the proteasome activator family, which mainly regulates the degradation and stability of proteins. Studies have shown that it plays crucial roles in lipid formation, stemness maintenance, and blood vessel formation. However, few studies have clarified the association between PA28γ and bone diseases. Herein, we identified PA28γ as a previously unknown regulator of bone homeostasis that coordinates bone formation and lipid accumulation. PA28γ-knockout mice presented with the characteristics of low bone mass and accumulation of lipids. Suppressed expression of PA28γ restrained the osteogenic differentiation and enhanced the adipogenic differentiation of bone marrow stromal cells (BMSCs). Overexpression of PA28γ promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs. Mechanistically, PA28γ interacted with Wnt5α, and the two interactors appeared to be positively correlated. PA28γ mainly activated the downstream Wnt/ß-catenin signaling pathway, which affects BMSCs differentiation homeostasis. Deletion of Wnt5α significantly delayed the promotion of osteogenic differentiation and partially alleviated the inhibitory effect of adipogenic differentiation of BMSCs in the PA28γ-overexpressing group. Furthermore, we demonstrated that PA28γ-knockout mice had an inhibited rate of bone healing in a drill-hole femoral bone defect model in vivo. Therefore, our results confirm the effects of PA28γ on bone formation and bone defect repair, indicating that PA28γ mainly interacts with Wnt5α to activate the Wnt/ß-catenin signaling pathway regulating BMSCs differentiation homeostasis. Our results reveal the function of PA28γ in bone diseases and provide a new theoretical basis for expanding the treatment of bone diseases.

Photobiomodulation Therapy and Pulp-Regenerative Endodontics: A Narrative Review.

Regenerative endodontic procedures (REPs) were used to recover the dental pulp's vitality in order to avoid the undesirable outcomes of conventional endodontic treatment and to promote dentinal formation, especially for immature permanent teeth. Photobiomodulation therapy (PBMT) exhibits photobiological and photochemical effects for improving the root canal's environmental conditions by compensating for oxidative stress and increasing the blood supply to implanted stem cells and improving their survival. Basic research has revealed that PBMT can modulate human dental pulp stem cells' (hDPSCs) differentiation, proliferation, and activity, and subsequent tissue activation. However, many unclear points still remain regarding the mechanisms of action induced by PBMT in REPs. Therefore, in this review, we present the applications of laser and PBMT irradiation to the procedures of REPs and in endodontics. In addition, the effects of PBMT on the regenerative processes of hDPSCs are reviewed from biochemical and cytological perspectives on the basis of the available literature. Furthermore, we consider the feasibility of treatment in which PBMT irradiation is applied to stem cells, including dental pulp stem cells, and we discuss research that has reported on its effect.

A CBCT Investigation of the Sella Turcica Dimension and Sella Turcica Bridging in Different Vertical Growth Patterns.

This study aimed to compare the sella turcica dimensions and sella turcica bridging (STB) via cone-beam computed tomography in different vertical patterns and then analyze the link between the sella turcica and vertical growth patterns. The CBCT images of 120 skeletal Class I subjects (an equal proportion of females and males; mean age of 21.46 years) were divided into three vertical growth skeletal groups. Student's t tests and Mann-Whitney U tests were used to assess the possible diversity in genders. The link between sella turcica dimensions and different vertical patterns was explored by one-way analysis of variance, as well as Pearson and Spearman correlation tests. The prevalence of STB was compared using the chi-square test. Sella turcica shapes were not linked to gender, but statistical differences were observed among different vertical patterns. In the low-angle group, a larger posterior clinoid distance and smaller posterior clinoid height, tuberculum sellae height, and dorsum sellae height were determined, and the incidence of STB was higher (p < 0.01). Sella turcica shapes were linked to vertical growth patterns, mainly involving the posterior clinoid process and STB, which could be used as an index to assess vertical growth trends.

LITTIP/Lgr6/HnRNPK complex regulates cementogenesis via Wnt signaling.

Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/ß-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/ß-catenin signaling via high expression of LGR6 promoted by HnRNPK.

Synthesis and acetylcholinesterase and butyrylcholinesterase inhibitory activities of 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives.

A series of novel 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives were synthesized. The cholinesterase inhibition assays indicated that most synthesized compounds exhibited good activity for acetylcholinesterase (AChE) and high selectivity index of AChE over butyrylcholinesterase (BuChE). Compound 12b exhibited the most potent AChE inhibitory activity with an IC(50) value of 0.068 µM and the highest selectivity index of 144. Kinetic study of AChE indicated that a mixed type of inhibition pattern existed for these indolizinoquinoline-5,12-dione derivatives. Molecular docking study indicated that compound 12b could bind to both the catalytically active site and the peripheral anionic site of AChE.

Progranulin is essential for bone homeostasis and immunology.

Intercellular communication or crosstalk between immune and skeletal cells is considered a crucial element in bone homeostasis modulation. Progranulin (PGRN) is an autocrine growth factor that is structured as beads-on-a-string and participates in multiple pathophysiological processes, including atherosclerosis, arthritis, neurodegenerative pathologies, cancer, and wound repair. PGRN functions as a competitor that binds to tumor necrosis factor receptor 1 (TNFR1), thereby blocking the TNF-α pathway. PGRN is regarded as an agonist of chondrogenesis and osteogenesis, delaying the progression of inflammation through the TNFR2 pathway. The exploitation of PGRN may bring benefits for inflammatory bone diseases and the stabilization of bone homeostasis. The PGRN-modified analog Atsttrin possesses three TNFR-binding fragments and thereby exerts superior therapeutic effects on multiple preclinical animal models compared to PGRN. In this review, we highlight the emerging roles of PGRN in bone formation, as well as in physiological and TNF-α-mediated inflammatory conditions revealed in recent discoveries. We address potential therapies for the treatment of inflammatory bone conditions, such as periodontitis, by the use of PGRN and its derivative Atsttrin.