Role and mechanism of macrophage-mediated osteoimmune in osteonecrosis of the femoral head / 中国修复重建外科杂志

OBJECTIVE@#To summarize the research progress on the role of macrophage-mediated osteoimmune in osteonecrosis of the femoral head (ONFH) and its mechanisms.@*METHODS@#Recent studies on the role and mechanism of macrophage-mediated osteoimmune in ONFH at home and abroad were extensively reviewed. The classification and function of macrophages were summarized, the osteoimmune regulation of macrophages on chronic inflammation in ONFH was summarized, and the pathophysiological mechanism of osteonecrosis was expounded from the perspective of osteoimmune, which provided new ideas for the treatment of ONFH.@*RESULTS@#Macrophages are important immune cells involved in inflammatory response, which can differentiate into classically activated type (M1) and alternatively activated type (M2), and play specific functions to participate in and regulate the physiological and pathological processes of the body. Studies have shown that bone immune imbalance mediated by macrophages can cause local chronic inflammation and lead to the occurrence and development of ONFH. Therefore, regulating macrophage polarization is a potential ONFH treatment strategy. In chronic inflammatory microenvironment, inhibiting macrophage polarization to M1 can promote local inflammatory dissipation and effectively delay the progression of ONFH; regulating macrophage polarization to M2 can build a local osteoimmune microenvironment conducive to bone repair, which is helpful to necrotic tissue regeneration and repair to a certain extent.@*CONCLUSION@#At present, it has been confirmed that macrophage-mediated chronic inflammatory immune microenvironment is an important mechanism for the occurrence and development of ONFH. It is necessary to study the subtypes of immune cells in ONFH, the interaction between immune cells and macrophages, and the interaction between various immune cells and macrophages, which is beneficial to the development of potential therapeutic methods for ONFH.

Fracture healing, the diamond concept under the scope: Hydroxyapatite and the hexagon / Consolidación de fractura, una mirada al concepto diamante: Hidroxiapatita y el hexágono

Abstract Bone healing after a fracture has many intercalated steps that depend on the host, type of injury, and often the orthopedist. The diamond concept since 2007 has outlined 4 main facets that have to be considered as a model by the treating surgeon at the time of injury and when nonunion develops: osteogenic cells, osteoconductive scaffolds, osteoinduction, and the biomechanical environment. All of these foment fracture healing in optimal circumstances. Yet, this work proposes other facets, such as osteoimmunology and vascularity, to be considered as well in the model. These are as important as the original four, though their correlation to the original work has been less noted until more recent literature. The mindset of the orthopedist must thoroughly analyze all these facets and many more when dealing with nonunion. This work presents, probably the most sig nificant ones, parting from the original 4-corner diamond model and expanding it to a more representative hexagon integrated model. Metaphorically, just like the strongest inorganic constituent of the bone: hydroxyapatite.

Resumen Hay múltiples pasos intercalados en la consolidación de la fractura que dependen del paciente, el tipo de fractura y frecuentemente del ortopedista. Desde su introducción en el año 2007, el concepto del diamante ha delineado 4 facetas o aristas principales que se han de tener en cuenta por el ortopedista en el momento de la lesión y cuando la no-unión de fractura ocurre: células osteogénicas, matrices osteocunductivas, osteoinducción, y el ambiente biomecánico. Otras facetas para tener en cuenta, no menos importantes, son la osteoimmunología y la vascularidad. Estas son tan importantes como las 4 facetas originales, pero la correlación entre las mismas ha sido poco notada o integrada hasta ahora. El ortopedista tratante debe analizar todas ellas en profundidad, especialmente cuando se trata de una no-unión. Este trabajo presenta las más significantes, partiendo del modelo original del diamante de 4 facetas hacia uno más representativo e integrado como el hexágono. Metafóricamente, como el elemento inorgánico más abundante y fuerte en el hueso: la hidroxiapatita.

Advances in immunoporosis / 中华内分泌代谢杂志

Osteoporosis is a common metabolic bone disease, which is involved in disrupted normal bone remodeling process and bone resorption exceeding bone formation. Osteoblasts and osteoclasts play critical roles in maintaining bone homeostasis. In recent years, more and more studies have found that immune cells are involved in the regulation of osteoblast and osteoclast activity via releasing various chemokines and cytokines, and the concept of immunoporosis has been proposed accordingly. This article summarizes the current state of knowledge on the immune system in the pathophysiology of osteoporosis, so as to study and prevent osteoporosis from the perspective of immunology.

Effect of Bushen Huatan Prescription on Serum LPS and TLR4/MyD88/NF-κB Signaling Pathway in Rats with Ovariectomy-induced Osteoporosis / 中国实验方剂学杂志

Objective:To explore the effect of Bushen Huatan prescription on serum lipopolysaccharide （LPS） and Toll-like receptor 4 （TLR4）/ myeloid cell differentiation protein 88 （MyD88）/nuclear transcription factor-<italic>κ</italic>B （NF-<italic>κ</italic>B） signaling pathway in rats with ovariectomy-induced osteoporosis. Method:Sixty SPF 6-month-old female rats were randomly divided into sham operation group， model group， estradiol valerate group and Bushen Huatan prescription low， medium and high dose groups.One week after modeling by bilateral ovariectomy， 8 rats in each group were selected to receive intragastric administration.The estradiol valerate group was given 0.184 mg·kg^-1 by gavage， and Bushen Huatan prescription low， middle and high dose groups were given 4.7， 9.4 and 18.8 g·kg^-1 by gavage， sham operation group and model group were given 0.9% saline 4 mL by gavage respectively.After 12 weeks of intervention， the rats were sacrificed for detection.Serum LPS was detected by enzyme linked immunosorbent assay （ELISA）， while protein expressions of TLR4， MyD88 and phosphorylated （p）-NF-<italic>κ</italic>B p65 in bone tissue were detected by Western blot， and the mRNA expressions of TLR4， MyD88， NF-<italic>κ</italic>B p65， IL-1<italic>β</italic>， and IL-6 in bone tissue were detected by quantitative real-time polymerase chain reaction（PCR）. Result:Compared with sham operation group， the serum LPS level as well as protein expression of TLR4， MyD88， p-NF-<italic>κ</italic>B p65 and mRNA expression of TLR4， MyD88， NF-<italic>κ</italic>B p65， IL-1<italic>β</italic>， and IL-6 significantly increased in model group（<italic>P</italic><0.05）.Compared with the model group， serum LPS level， protein expression of TLR4， MyD88， and p-NF-<italic>κ</italic>B p65， mRNA levels of TLR4， MyD88， and NF-<italic>κ</italic>B p65 in bone tissues as well as downstream inflammatory factors IL-1<italic>β</italic>， IL-6 mRNA expression decreased to different degrees in estradiol valerate group and Bushen Huatan prescription high dose group（<italic>P</italic><0.05）. Conclusion:Bushen Huatan prescription can reduce serum LPS content， regulate mRNA and protein expression of TLR4， MyD88， NF-<italic>κ</italic>B p65 and p-NF-<italic>κ</italic>B p65 in TLR4/MyD88/NF-<italic>κ</italic>B pathway， and down-regulate mRNA levels of IL-1<italic>β</italic> and IL-6 in bone tissues to improve bone microstructure and inhibit the development of postmenopausal osteoporosis （PMOP）.

Mechanism of Bushen Huatan Prescription in Regulating Th17/Treg Balance in Ovariectomized Osteoporosis Rats / 中国实验方剂学杂志

Objective:To study the effect of Bushen Huatan prescription on helper T cell 17 （Th17）/T regulatory cells （Treg） balance of immune T cell subsets in the prevention and treatment of postmenopausal osteoporosis. Method:Sixty 6-month-old female SD rats were randomly divided into sham operation group， model group， estradiol valerate group （0.184 mg·kg^-1） and Bushen Huatan prescription low， medium and high groups （4.7， 9.4， 18.8 g·kg^-1） according to the random number table. All the groups except the sham operation group received ovariectomy to make postmenopausal osteoporosis model. Intragastric administration was started 1 week after operation， and the rats in model group and sham operation group received equal volume of normal saline， once a day for 12 weeks. Microcomputed tomography （Micro CT） was then used to detect bone mass and microstructure of rats， the contents of Forkhead box protein （Foxp3） and retinoic acid related nuclear orphan receptor （ROR<italic>γ</italic>t） in serum were detected by enzyme-linked immunosorbent assay （ELISA）， the mRNA expression levels of Foxp3 and ROR<italic>γ</italic>t in bone tissues were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot was used to detect the protein expression of Foxp3 and ROR<italic>γ</italic>t in bone tissues， the number of Th17 and Treg cells in each group was analyzed and compared by flow cytometry. Result:Compared with the sham operation group， the bone mass and trabeculae of the model group decreased （<italic>P</italic><0.01）， the bone microstructure was destroyed， the concentration of Foxp3 in serum decreased， the concentration of ROR<italic>γ</italic>t increased （<italic>P</italic><0.01）， the mRNA and protein expression levels of Foxp3 in bone tissues decreased， ROR<italic>γ</italic>t increased， the number of Treg cells in bone tissues decreased， number of Th17 cells increased （<italic>P</italic><0.01）， and Th17/Treg ratio increased （<italic>P</italic><0.01） in model group. Compared with the model group， the bone mass in each treatment group increased （<italic>P</italic><0.05， <italic>P</italic><0.01）， Foxp3 concentration in serum increased， ROR<italic>γ</italic>t concentration decreased （<italic>P</italic><0.01）， the mRNA and protein expression levels of Foxp3 in bone tissues increased significantly （<italic>P</italic><0.05， <italic>P</italic><0.01）， but no statistical difference was shown in mRNA expression between low dose group and the model group. In addition， the mRNA and protein expression of ROR<italic>γ</italic>t decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）， number of Treg cells increased， number of Th17 cells decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）， and Th17/Treg ratio decreased in treatment groups （<italic>P</italic><0.01）. Conclusion:Bushen Huatan prescription can increase bone mass， improve bone microstructure， increase the number of Treg cells and decrease the number of Th17 cells in ovariectomized rats. It is concluded that Bushen Huatan prescription may play a role in preventing and treating postmenopausal osteoporosis by regulating Th17/Treg balance.

Research progress on the Hippo-YAP signaling pathway mediated osteoimmunology in modulating implant osseointegration / 口腔疾病防治

@#Ideal osseointegration is intimately related to favorable osteoimmune properties around dental implants. An increasing number of in vitro and in vivo studies have indicated that the Hippo-YAP signaling pathway is involved in this biological process. In this article, the implicated roles of Hippo-YAP the signaling axis in peri-implant osteoimmunology were summarized by reviewing relevant evolving literature. The discrepancy concerning the Hippo-YAP signaling regulatory effect on osteogenesis and polarization direction were analyzed as well as propose the potential mechanism, which may be caused by the maturation of osteogenesis-related cells and heterogeneity of macrophages. More attention should be given to the requirements of promoting osteogenesis and patterns of regulating the immune microenvironment by Hippo-YAP in future studies.

Effect of different orthodontic forces on the expression of T helper cell 17 cell-related cytokines in the pressure side of periodontal tissue in rats / 华西口腔医学杂志

OBJECTIVES@#This study aimed to explore the changes in the expression of the characteristic transcription factor retinoid related orphan receptor γt (RORγt) and the cytokine interleukin-17 (IL-17) of T helper cell 17 (Th17) in the pressure side of the periodontal tissue of rats under different orthodontic forces. Their effects on the expression of osteoprotegerin (OPG) and the quantity of osteoclast (OC) were also explored. The role of Th17 cell in alveolar bone remodeling under different forces was preliminarily investigated.@*METHODS@#A total of 108 rats were chosen and randomly divided into three groups. Mesial forces of 0, 50, and 100 g were loaded on the maxillary first molar in the three groups. The rats were executed at 0, 1, 3, 5, 7, and 14 days. The expression of RORγt mRNA was quantified by real-time quantitative polymerase chain reaction. The expression of IL-17 protein was quantified by enzyme linked immunosorbent assay. The expression levels of RORγt and OPG proteins were quantified, and the quantity of OC was counted via immunohistochemistry.@*RESULTS@#The expression levels of RORγt and IL-17 and the quantity of OC increased first and then decreased in the 50 and 100 g groups, and the peak values of the two groups were on days 5 and 7, respectively. The expression levels in the 50 g group basically recovered to normal level on day 14, while that in the 100 g group remained at a high level. The expression levels in the 50 g group were higher than those in the 0 g group and lower than those in the 100 g group. The expression of OPG in the 50 g group decreased first, then increased, and finally decreased. It basically recovered to normal level on day 14. The expression of OPG in the 100 g group decreased first and then increased. It remained at a high level on day 14. The expression in the 50 g group was significantly higher than that in the 0 g group on day 7, while the expression in the 100 g group was significantly higher than that in the 0 g group on day 14.@*CONCLUSIONS@#RORγt, IL-17, and OPG were expressed regularly over time under different orthodontic forces, indicating that Th17 participated in the process of bone resorption on the pressure side of periodontal tissue by secreting IL-17.

The role of helper T cell in the pathogenesis of osteoarthritis / 中国修复重建外科杂志

Objective: To review and summarize the role of helper T cell (Th) in the pathogenesis of osteoarthritis (OA) and research progress of Th cell-related treatment for OA. Methods: The domestic and foreign literature in recent years was reviewed. The role of Th cells [Th1, Th2, Th9, Th17, Th22, and follicular helper T cell (Tfh)] and related cytokines in the pathogenesis of OA and the latest research progress of treatment were summarized. Results: Th cells play an important role in the pathogenesis of OA. Th1, Th9, and Th17 cells are more important than Th2, Th22, and Tfh cells in the pathogenesis of OA. Cytokines such as tumor necrosis factor α and interleukin 17 can cause damage to articular cartilage significantly. Conclusion: At present, the role of Th cells in the pathogenesis of OA has been played in the spotlight. The specific mechanism has not been clear. Regulating the Th cell-associated cytokines, intracellular and extracellular signals, and cellular metabolism is a potential method for prevention and treatment of OA.

Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4+ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

Regulation of Osteoclast Differentiation by Cytokine Networks

Cytokines play a pivotal role in maintaining bone homeostasis. Osteoclasts (OCs), the sole bone resorbing cells, are regulated by numerous cytokines. Macrophage colony-stimulating factor and receptor activator of NF-κB ligand play a central role in OC differentiation, which is also termed osteoclastogenesis. Osteoclastogenic cytokines, including tumor necrosis factor-α, IL-1, IL-6, IL-7, IL-8, IL-11, IL-15, IL-17, IL-23, and IL-34, promote OC differentiation, whereas anti-osteoclastogenic cytokines, including interferon (IFN)-α, IFN-β, IFN-γ, IL-3, IL-4, IL-10, IL-12, IL-27, and IL-33, downregulate OC differentiation. Therefore, dynamic regulation of osteoclastogenic and anti-osteoclastogenic cytokines is important in maintaining the balance between bone-resorbing OCs and bone-forming osteoblasts (OBs), which eventually affects bone integrity. This review outlines the osteoclastogenic and anti-osteoclastogenic properties of cytokines with regard to osteoimmunology, and summarizes our current understanding of the roles these cytokines play in osteoclastogenesis.

Host response mechanisms in periodontal diseases

Periodontal diseases usually refer to common inflammatory disorders known as gingivitis and periodontitis, which are caused by a pathogenic microbiota in the subgingival biofilm, including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola that trigger innate, inflammatory, and adaptive immune responses. These processes result in the destruction of the tissues surrounding and supporting the teeth, and eventually in tissue, bone and finally, tooth loss. The innate immune response constitutes a homeostatic system, which is the first line of defense, and is able to recognize invading microorganisms as non-self, triggering immune responses to eliminate them. In addition to the innate immunity, adaptive immunity cells and characteristic cytokines have been described as important players in the periodontal disease pathogenesis scenario, with a special attention to CD4+ T-cells (T-helper cells). Interestingly, the T cell-mediated adaptive immunity development is highly dependent on innate immunity-associated antigen presenting cells, which after antigen capture undergo into a maturation process and migrate towards the lymph nodes, where they produce distinct patterns of cytokines that will contribute to the subsequent polarization and activation of specific T CD4+ lymphocytes. Skeletal homeostasis depends on a dynamic balance between the activities of the bone-forming osteoblasts (OBLs) and bone-resorbing osteoclasts (OCLs). This balance is tightly controlled by various regulatory systems, such as the endocrine system, and is influenced by the immune system, an osteoimmunological regulation depending on lymphocyte- and macrophage-derived cytokines. All these cytokines and inflammatory mediators are capable of acting alone or in concert, to stimulate periodontal breakdown and collagen destruction via tissue-derived matrix metalloproteinases, a characterization of the progression of periodontitis as a stage that presents a significantly host immune and inflammatory response to the microbial challenge that determine of susceptibility to develop the destructive/progressive periodontitis under the influence of multiple behavioral, environmental and genetic factors.

Osteoimmunology: A Brief Introduction

Recent investigations have demonstrated extensive reciprocal interactions between the immune and skeletal systems, resulting in the establishment of osteoimmunology as a cross-disciplinary field. Here we highlight core concepts and recent advances in this emerging area of study.

Principios básicos de la osteoinmunología en las enfermedades reumáticas / Basic principles of osteoimmunology in rheumatic diseases

El estudio de la inmunología ósea va adquiriendo cada vez mayor relevancia en la comprensión de las enfermedades reumatológicas y sus potenciales manejos. El conocimiento de la estructura y función ósea de los distintos tipos de tejidos óseos, así como las vías clave involucradas en los procesos de osificación y remodelación ósea, son hoy en día puntos fundamentales para entender y proponer nuevos tratamientos. Mediante el estudio de la osteoinmunología se ha logrado explicar procesos característicos de las enfermedades reumatológicas, como lo son las erosiones óseas yuxta-articulares, la osteoporosis periarticular y sistémica, además de la neoformación de hueso que ocurre en enfermedades como la espondilitis anquilosante o la osteoartritis. A continuación se expone una revisión detallada de los conocimientos actuales en osteoinmunología.

The study of osteoimmunology is gaining increasing importance in the understanding of rheumatic diseases and their potential treatments. The knowledge of the bone structure and function of the different types of bone tissues, as well as the key pathways involved in the processes of ossification and bone remodeling, are now key points in the understanding and the development of new treatments. The osteoimmunology has explained different processes that are characteristic in the rheumatic diseases, such as juxta-articular bone erosions, periarticular and systemic osteoporosis, as well as the new bone formation that occurs in diseases such ankylosing spondylitis or osteoarthritis. In this presentation, it will be presented a detailed review of the current knowledge in osteoimmunology.

Osteoclasts and T-helper cells / 国际儿科学杂志

The interaction between T cell and osteoclasts is important in osteoimmunology.T-helper cells,which produce interleukin-17,induce the expression of receptor activator of nuclear factor κB ligand in synovial cells.Companied by with inflammatory cytokines,they stimulate the differentiation and activation of osteoclasts.Osteoimmunology helps us understand how antirheumatic drugs work,as well as developing new therapeutic strategies for rheumatic diseases.

Osteoimmunology of postmenopausal osteoporosis / 中华内分泌代谢杂志

Postmenopausal osteoporosis can be classified as an inflammatory, or even an autoimmune condition, hence new therapeutic " immune" targets. Some recently published works in this area are summarized, which may help to find a noval strategy for the treatment and prevention of postmenopausal osteoporosis.

Osteoimunologia aplicada às reconstruções maxilofaciais: [revisão] / Osteoimmunology applied to maxillofacial reconstruction: [review]

Esta revisão de literatura teve por objetivo discutir os aspectos atuais da osteoimunologia aplicada às reconstruções maxilofaciais. As reabilitações maxilares por implantes podem demandar enxertia óssea para prévia adequação do rebordo à colocação do implante. Os enxertos ósseos alógenos têm sido introduzidos nesse protocolo para evitar cirurgia numa segunda área. A criopreservação figura como um método importante para diminuir a antigenicidade do tecido, mas outras técnicas podem ser exemplificadas como a esterilização por radiação gama ou óxido de etileno. A imunologia participa do processo de incorporação ou de rejeição dos enxertos ósseos incrementando sua absorção. Diversas moléculas, como as interleucinas, o ligante do receptor ativador do fator nuclear-κβ (RANKL), o fator nuclear de células T ativadas (NFAT), o fator estimulador de colônias de macrófagos (M-CSF), o fator de células B jovens (EBF-2) e a osteoprotegerina estabelecem a relação entre as células imunológicas e o metabolismo do osso enxertado. As evidências obtidas da literatura permitem inferir que o osso alógeno congelado é um bom material para aposição dos maxilares por não induzir rejeição imunológica.

This literature review aimed to discuss some current aspects related to osteoimmunology applied to maxillofacial reconstruction. Maxillary rehabilitation with implants may demand bone grafting before implant placement in the alveolar ridge. Allografts have been introduced to prevent surgery in a secondary area. Cryopreservation is an important method to decrease tissue antigenicity, but other techniques can also be used such as sterilization by gamma radiation or ethylene oxide. Immunology may participate in the incorporation or rejection process of bone grafts by increasing bone resorption. Several molecules, such as interleukins, receptor activators of nuclear factor κβ ligand RANKL, nuclear factor of activated T cells (NFAT), macrophage-colony stimulating factor (M-CSF), early B cell factor (EBF-2), and osteopontegrin establish the relation between immunological cells and bone graft metabolism. Evidences from the literature suggest that frozen allogenic bone may be a good material for jaw onlay grafts since they do not induce immunological rejection.