MicroRNA在强直性脊柱炎成骨、破骨机制中的作用

炎性骨破坏和新骨形成是强直性脊柱炎(ankylosing spondylitis,AS)的典型病理改变,AS早期以炎症为主,晚期出现异位骨化和骨破坏,异位骨化和骨破坏两种矛盾的表现反映了强直性脊柱炎患者成骨与破骨过程之间的动态平衡被打破。其发病机制尚不完全清楚,目前研究认为,AS复杂的新骨形成机制与Wnt/β-catenin信号通路及BMP/Smads通路密切相关,而破骨细胞则在骨破坏过程中起重要作用,RANKL/RANK/OPG系统中的细胞因子是调控破骨细胞分化成熟的关键因子。Micro RNA可调节成骨细胞、软骨细胞和破骨细胞的分化与功能,是骨形成、骨吸收、骨重塑和修复过程中的关键调节因子。研究MicroRNA在强直性脊柱炎成骨、破骨机制中的作用,可为AS的诊断和治疗提供新的依据。     

骨质疏松症对脊柱小关节退变的影响

骨质疏松症(OP)以骨量减少和骨的微细结构破坏为主要特征,并伴随骨质脆性增加和骨折危险性升高.由于骨的结构破坏,可引发脊柱退行性变,使椎体高度丢失应力改变及使人体成骨、破骨细胞代谢紊乱,发生脊柱尤其是腰椎小关节退变.但由骨质疏松症引起脊柱小关节退变尤其是腰椎小关节退变原因发病机制文献报道较少,目前认为骨质疏松对脊柱小关节退变与成骨,破骨细胞代谢影响,及发生椎体内微骨折,改变椎体高度及软骨下骨血供应微环境,增加小关节应力,减少其血供营养有关.     

破骨细胞介导炎症性骨丢失的研究进展

破骨细胞起源于骨髓的多潜能干细胞,破骨细胞的数量和功能决定了关节破坏与骨丢失的严重程度,而炎症本身并不介导关节破坏和骨丢失。炎症性关节的滑膜成纤维细胞产生大量的炎症因子,如肿瘤坏死因子-α(TNF-α)和白介素-1(IL-1)。这些炎症因子不仅诱发炎症反应,而且通过促进核因子κB受体激活子配体,间接或直接增加破骨细胞的生成,并促进其功能,从而将炎症反应与局部骨丢失及损坏联系在一起。本文综述了近年来关于TNF-α、IL-1及破骨细胞靶疗法在破骨细胞介导的炎症性骨丢失过程中的研究进展。TNF-α通过促进外周血破骨细胞前体细胞的分化直接影响关节局部成熟破骨细胞的最终数目,而IL-1主要通过延长成骨细胞的寿命及调控破骨细胞骨架的重组来增加其骨吸收能力。抑制破骨细胞生长及功能的破骨细胞靶疗法在治疗炎症性骨丢失和关节损伤等方面日益得到重视。     

RANKL/RANK信号途径与类风湿关节炎骨量丢失的相关性

类风湿关节炎（rheumatoid arthritis,RA）是一种慢性全身性自身免疫性疾病,临床上抑制RA患者关节周围及全身的骨量丢失是治疗的关键。研究表明炎症细胞因子（TNF-α、IL-1、IL-7、IL-17等)是刺激导致RA患者骨量丢失的重要介质,破骨细胞是参与骨吸收的主要细胞,RANKL/RANK信号途径是RA炎症导致骨量丢失的主要通路。RANKL/RANK信号途径为以RA为代表的自身免疫性疾病与骨代谢疾病之间建起了一座桥梁,其在免疫系统和破骨细胞发育中的关键作用已经形成了“骨免疫”理论,以更准确的揭示在RA继发骨量丢失的过程中免疫系统与骨代谢系统间复杂的交互作用。本文综述了RA继发骨量丢失与RANKL/RANK信号途径间的相关性。     

RANKL/RANK信号途径与类风湿关节炎骨丢失的相关性

类风湿关节炎(rheumatoid arthritis,RA)是一种慢性全身性自身免疫性疾病,临床上抑制RA患者关节周围及全身的骨丢失是治疗的关键.研究表明炎症细胞因子(TNF-α,IL-1,IL-7,IL-17等)是刺激导致RA患者骨丢失的重要介质,破骨细胞是参与骨吸收的主要细胞,RANKL/RANK信号途径是RA炎症导致骨丢失的主要通路.RANKL/RANK信号途径为以RA为代表的自身免疫性疾病与骨代谢疾病之间建起了一座桥梁,其在免疫系统和破骨细胞发育中的关键作用已经形成了"骨免疫"理论,以更准确的揭示在RA继发骨丢失的过程中免疫系统与骨代谢系统间复杂的交互作用.本文综述了RA继发骨丢失与RANKL/RANK信号途径间的相关性.     

破骨细胞的骨吸收机制

破骨细胞是一种巨大的多核细胞,起源于单核巨噬细胞/单核系造血前体细胞,在骨吸收过程中发挥重要作用。破骨细胞的形成和活性异常可导致骨质疏松、类风湿关节炎、关节置换后假体无菌性松动等许多疾病,因此破骨细胞是治疗这些疾病的靶点之一。目前对破骨细胞的分化形成研究较多,但对破骨细胞如何识别、降解骨组织方面的研究较少。骨盐被认为是破骨细胞识别的重要成分,但是近年来的研究发现骨基质不是破骨细胞激活的必需成分,玻连蛋白包被的培养皿也能使破骨细胞出现骨吸收的特有形态,玻连蛋白对破骨细胞的激活有重要的作用。此外,最近的研究证明骨基质降解产物的吞入和分泌对破骨细胞的分化和功能的保持有重要意义。这些分子机制的研究可能为骨骼疾病提供新的治疗靶点。     

骨骼疾病巨噬细胞与破骨细胞交互作用的研究进展

骨免疫学认为巨噬细胞和破骨细胞之间的相互作用可以调控骨骼疾病，巨噬细胞-破骨细胞轴在骨免疫中发挥重要作用。人工关节产生的磨损颗粒刺激破骨细胞发生骨溶解，巨噬细胞吞噬磨损颗粒产生慢性炎症导致无菌性松动的发生。而巨噬细胞通过抗炎作用和促进破骨细胞分化促使骨折愈合。破骨细胞活跃是骨质疏松发生的主要原因，巨噬细胞在其中扮演重要的角色。同时巨噬细胞被认为是类风湿性关节炎患者破骨细胞过度活跃的重要原因。本文就骨免疫中巨噬细胞和破骨细胞的相互作用在相关骨骼疾病中的作用进行综述。     

破骨细胞研究新进展

破骨细胞是起源于骨髓单核细胞的多核细胞,成熟的破骨细胞位于骨小梁和骨皮质内表面。骨组织稳态受成骨细胞产生的骨形成和破骨细胞引起的骨吸收之间的平衡调节。然而在病理状态下,多种因素,包括肿瘤坏死因子超家族配体和炎性蛋白质等都促进破骨细胞的形成,使骨代谢失去平衡,导致骨组织过度吸收和过度形成。破骨细胞过度活化常见于骨质疏松症,自身免疫性关节炎等骨代谢疾病。破骨细胞功能障碍同样会导致如石骨症等疾病。因此,破骨细胞是骨代谢疾病预防和治疗方面的重要靶点。随着研究的深入,近年来有关破骨细胞的研究有了新的发现。本文就破骨细胞最新研究进展做一综述。     

破骨细胞与骨质疏松症的关系研究进展

破骨细胞是一种巨大的多核细胞,它的形成和活性异常可导致骨质疏松、类风湿关节炎、关节置换后假体无菌性松动等许多疾病;骨质疏松症是一种多因素导致的全身代谢性骨骼疾病,其治疗靶点主要集中在抑制破骨细胞的活性及促进成骨细 胞的形成方面,随着破骨细胞对骨作用的信号通路等骨生物学研究的深人,一些新的治疗靶点被陆续发现;目前,0PG/, RANKL /RANK信号通路、肿瘤坏死因子信号通路、一氧化氮和雌激素、过氧化物酶体增殖物激活受体γ、小眼畸形相关转录因子等信号通路认为与破骨细胞关系密切,本文就破骨细胞与骨质疏松症关系作一综述,为骨质疏松症的防治提供相关依据。     

基质金属蛋白酶和细胞因子在强直性脊柱炎骨破坏中的作用

强直性脊柱炎(ankylosing spondylitis,AS)是以中轴关节慢性炎症为主的原因不明的全身性免疫性疾病。其特点为几乎全部累及骶髂关节,常发生椎间盘纤维环及其附近韧带钙化和骨性强直,也可累及外周关节并造成关节软骨及骨的破坏,晚期可发生脊柱及外周关节强直、畸形以致严重功能受损[1]。所以我们必须强调重视AS骨质破坏发生机制的研究,有利于寻找有效药物,减少致残。1骶髂关节炎组织学研究较系统的骶髂关节炎组织学研究表明,AS的5个阶段不同程度存在滑膜炎、骨髓黏液样变、浅表软骨破坏、肌腱端炎、关节内纤维赘、新骨形成和骨性强直等众多病理表现;其中滑膜炎和软骨下骨髓黏液样变较肌腱端炎更能合理解     

Impact of Inflammation on the Osteoblast in Rheumatic Diseases

Normal bone remodeling depends upon a balance between the action of bone-resorbing cells, osteoclasts, and bone-forming cells, osteoblasts. When this balance is disrupted, as is seen in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS), abnormal bone loss or bone formation occurs. In RA, proinflammatory cytokines induce osteoclast differentiation and inhibit osteoblast maturation, leading to articular bone erosions. In contrast, the inflammatory milieu in AS leads to excessive osteoblast activation and bone formation at sites of entheses. While much information exists about the effects of proinflammatory cytokines on osteoclast differentiation and function, more recent studies have begun to elucidate the impact of inflammation on the osteoblast. This review will summarize the mechanisms by which inflammation perturbs bone homeostasis, with a specific focus on the osteoblast.     

Abnormal bone remodelling in inflammatory arthritis

Osteopenia is responsible for substantial comorbidity in patients suffering from rheumatoid arthritis and is an important factor in the surgical management of joint disease. In animal models of bone loss stimulated by inflammatory arthritis, increased bone remodelling and altered microstructure of bone have been documented. The subchondral bone plate near the joint surface is narrow and perforated by vascular inflammatory invasion, and in the shaft the thin cortices are weakened by giant resorption defects. Biomechanical tests and a mathematical model of bone strength suggest that cortical defects, much larger than those found in normal osteonal remodelling, are principally responsible for the experimentally observed loss of strength. Similarly, these defects may explain the increased femoral fracture risk in rheumatoid arthritis.The osteoclast, the cell resorbing bone, is demonstrated in increased number and activity in rheumatoid arthritis and in animal models. Bisphosphonates, drugs that inhibit osteoclast function, have been shown experimentally to reduce both focal and generalized osteopenia and to prevent loss of bone strength. Bisphosphonates also protect articular cartilage from damage characteristic of inflammatory arthritis. The mechanism of chondroprotection may be prevention of subchondral bone resorption by the osteoclast and also an altered distribution of bone marrow cells. Thus, bisphosphonates, currently in clinical use for other bone metabolic diseases, appear to have potential as prophylaxis and treatment for osteopenia and joint damage in inflammatory arthritis.     

Regulation of osteoclast differentiation and function by phosphate: potential role of osteoclasts in the skeletal abnormalities in hypophosphatemic conditions.

Mice fed with a low Pi diet exhibited decreased osteoclast number. Hyp mice also showed decreased osteoclasts, and high Pi reversed it. Low Pi reduced osteoclast formation and bone resorption in vitro. Hypophosphatemia may suppress osteoclast differentiation/function, leading to skeletal abnormalities. INTRODUCTION: Skeletal abnormalities seen in hypophosphatemic disorders indicate a critical role of phosphate (Pi) in skeletogenesis. However, the role of osteoclasts in the pathogenesis of the disturbed skeletogenesis is unclear. MATERIALS AND METHODS: Mice fed with a low-Pi diet and Hyp mice that are characterized by hypophosphatemia and impaired osteogenesis were studied. Effects of Pi on osteoclast formation and bone resorption were also examined in vitro. RESULTS: Histomorphometric examination showed that mice on a low-Pi diet exhibited decreased osteoclast number. Furthermore, osteoclast number in Hyp mice was also decreased compared with wildtype (WT) mice. Of note, feeding of Hyp mice with high-Pi diet significantly reversed hypophosphatemia, improved disturbed osteogenesis, and increased osteoclast number. Osteoclast-like cell (OLC) formation and bone resorption in Hyp bone marrow cells was not different from WT bone marrow cells. On the other hand, OLC formation and bone resorption were decreased in conjunction with reduced mRNA expression of RANKL in WT bone marrow cells cultured in the medium containing low Pi (0.5 mM). Recombinant human matrix extracellular phosphoglycoprotein (MEPE), a candidate for phosphatonin, also decreased osteoclast formation, whereas fibroblast growth factor 23 (FGF23), another phosphatonin candidate, showed no effects. CONCLUSIONS: Our results suggest that Pi controls the differentiation and function of osteoclasts. These actions of Pi on osteoclasts may be associated with the pathogenesis of the skeletal abnormalities in hypophosphatemic disorders.     

Signaling axis in osteoclast biology and therapeutic targeting in the RANKL/RANK/OPG system

Bone integrity is maintained through a balance between bone formation and bone resorption, and osteoclasts are primary cells involved in bone resorption. Recent studies have revealed an essential role of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) in the development of osteoclasts, and detailed molecular cascades that induce osteoclast differentiation, activation and apoptosis have been clarified. Osteoclasts are involved in various pathologic conditions, such as osteoporosis, rheumatoid arthritis and tumor-induced bone disease, which are characterized by abnormal bone resorption, and the finding of RANKL has provided us a good therapeutic target for such pathologic conditions.     

Pathways for Bone Loss in Inflammatory Disease

Chronic inflammation including autoimmune disease is an important risk factor for the development of osteoporosis. Receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play a central role in osteoclast differentiation and function, and the molecular pathways by which M-CSF and RANKL induce osteoclast differentiation have been analyzed in detail. Proinflammatory cytokines directly or indirectly regulate osteoclastogenesis and bone resorption providing a link between inflammation and osteoporosis. Tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17 are the most important proinflammatory cytokines triggering inflammatory bone loss. Inhibition of these cytokines has provided potent therapeutic effects in the treatment of diseases such as rheumatoid arthritis. Further investigation is needed to understand the pathophysiology and to develop new strategies to treat inflammatory bone loss. This review summarizes new data on inflammatory bone loss obtained in 2011.     

Increased expression of carbonic anhydrase I in the synovium of patients with ankylosing spondylitis

Background  

One of the most distinctive features of ankylosing spondylitis (AS) is new bone formation and bone resorption at sites of chronic inflammation. Previous studies have indicated that the hyperplasia and inflammation of synovial tissues are significantly related to the pathogenic process of AS. The present study used a proteomic approach to identify novel AS-specific proteins by simultaneously comparing the expression profiles of synovial membranes from patients with AS, rheumatoid arthritis (RA) and osteoarthritis (OA).     

Osteoporosis in inflammatory joint diseases

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are two inflammatory joint diseases characterized by bone complications including osteoporosis. In RA, periarticular bone loss, bone erosions, and systemic osteoporosis are observed, with an increased risk of fractures. Determinants of fractures are underlying conditions (as RA has a female preponderance and an increased prevalence with age), severity of the disease, and use of glucocorticoids. However, bone loss can occur even in glucocorticoid-naive patients. Prospective data show that the optimal control of inflammation in RA is associated with decrease in structural damage and bone loss. RA illustrates the role of inflammation on bone resorption. In AS, osteoporosis is an early event and vertebral fracture risk is increased. Bone loss is related mainly to inflammation, as the disease can occur in young male adult populations, and glucocorticoids are not used in this disease. However, AS is characterized by progressive stiffness and ankylosis of the spine and illustrates also the potential role of inflammation on local bone formation.     

Juxtaarticular bone loss in experimental inflammatory arthritis

The osteopenia associated with experimental inflammatory arthritis was studied by a histomorphometric method that exphasized net changes in bone composition. Juxtaarticular trabecular bone volume and turnover were studied in the carrageenan injection model of inflammatory arthritis of the mature rabbit knee. Trabecular bone volume was studied by histomorphometry of the femoral condyles and confirmed by photodensitometry on standard macroradiographs. Osteogenesis was studied by imaging of calcein fluorochrome-labeled newly formed bone in undecalcified histological sections. A significant net loss of cancellous bone (approximately 20%) occurred over 49 days in both the medial and the lateral femoral condyle in the arthritis group compared with normal controls. Total osteogenesis was increased fourfold and it was calculated that an even greater increase in total bone resorption was responsible for the negative bone balance. There is evidence that the periarticular bone loss of human rheumatoid arthritis is also associated with increased bone turnover. Quantitative studies of the kinetics of bone remodeling in inflammatory arthritis will provide the basis for therapeutic attempts to prevent or reverse arthritis-induced bone loss. Fracture risk in inflammatory arthritis may be increased not only by osteopenia, but additionally by the presence of a large proportion of newly formed (and presumably less mineralized) bone.     

Histomorphometric assessment of bone changes in rats with type II collagen-induced arthritis.

Numerous studies have demonstrated bone loss in rats following immobilization by tenotomy or nerve sectioning and following ovariectomy. However, few experiments have focused on bone change in rats with arthritis. We investigated bone loss in the proximal tibia and lumbar vertebra in rats with type II collagen-induced arthritis, an experimental model of rheumatoid arthritis, using histomorphometry. Bone loss in the early phase after immunization reflected a significant increase in numbers of osteoclasts and temporarily decreased bone formation. In the proximal tibia, near an arthritic joint, osteoclast numbers associated with bone trabeculae were increased four times over control numbers 4 weeks after immunization. In the lumbar vertebra, where arthritis was not shown, recruitment of osteoclasts occurred later than in the proximal tibia. With time, in both the proximal tibia and lumbar vertebra bone resorption normalized, but bone formation rate and double-label surface by tetracycline, a parameter reflecting bone formation, were increased above control values. We conclude that differences between the proximal tibia and lumbar vertebra probably reflected resumption of function as well as distance from areas of inflammation. These findings indicate that collagen-induced arthritis in rats is a useful model not only of autoimmunity, but also of juxta-articular and generalized osteoporosis in rheumatoid arthritis.