选择性雌激素受体调节剂对骨关节炎作用的研究进展

目的综述选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)对骨关节炎(osteoarthritis,OA)作用的研究进展。方法广泛查阅国内外有关雌激素和SERMs对OA作用效果及作用机制的有关文献,并进行综述。结果SERMs阻止OA软骨和软骨下骨破坏,减轻滑膜炎,维持关节健康,并在一定程度上改善OA样关节退变,延缓OA关节的破坏。结论 SERMs对OA关节具有保护作用,有望成为OA调修药的候选药物,但仍需完善相关的基础和临床研究,明确SERMs对OA的作用机制。     

甲状旁腺激素和甲状旁腺激素相关蛋白在正常及骨性关节炎软骨中作用机制的研究进展

目的综述在正常和骨性关节炎(osteoarthritis,OA)的关节软骨及软骨下骨中,甲状旁腺激素(parathyroid hormone,PTH)和甲状旁腺激素相关蛋白(parathyroid hormone-related protein,PTHrP)的作用机制研究进展。方法广泛查阅近年来有关PTH和PTHrP对正常和OA关节软骨作用机制的文献,并进行总结与分析。结果 PTH和PTHrP可抑制OA软骨细胞的肥大分化及凋亡,促进其增殖,从而对OA软骨细胞起到保护作用;OA软骨下骨成骨细胞对PTH的反应下降。结论 PTH、PTHrP可能通过多种信号通路参与软骨降解和软骨下骨重塑,并对OA进展起到延缓和保护作用。     

软骨下骨在骨关节炎进展中的作用

骨关节炎(OA)以关节软骨进行性退变和软骨下骨反应性增生为主要病理特征.关节软骨损害是OA最明显变化,OA研究长期以来主要集中在关节软骨,但软骨下骨作为与之毗邻的组织,在OA发病中的作用不容忽视,认清软骨下骨在OA中的变化和作用,有助于更全面和深刻地认识OA发病机制,为治疗提供新思路.该文就软骨下骨在OA中的病理变化及OA进展中的作用作一综述.     

以软骨下骨硬化为靶点的骨关节炎治疗研究进展

骨关节炎(OA)是以关节软骨退变、软骨下骨硬化为主要特征的关节退行性疾病。病理特点为关节软骨变性破坏、软骨下骨硬化或囊性变、关节边缘骨质增生、滑膜病变、关节囊挛缩、韧带松弛或挛缩、肌肉萎缩无力等。近年来研究发现软骨下骨硬化是OA的一个病因,软骨下骨硬化优于并加速软骨退变,进而加速OA的发生发展。抑制或延缓软骨下骨硬化对于OA的治疗具有重大的意义。本文针对以软骨下骨硬化为靶点的OA治疗研究进展进行综述,为后续基础研究及临床工作提供帮助。     

阿仑膦酸钠对前交叉韧带切断大鼠关节软骨退变的影响

[目的]观察阿仑膦酸钠(alendronate,ALN)对前交叉韧带切断术(anterior cruciate ligament transaction,ACLT)后骨关节炎模型大鼠膝关节软骨和软骨下骨的影响.[方法]24只3个月龄雌性SD大鼠按体重随机分为假手术组(Sham,n=8)、手术组(ACLT+NS,n=8)及给药组(ACLT+ALN,n=8),术后ALN组给予阿仑膦酸钠20 μg·kg-1·2 d-1皮下注射,连续给药12周;ACLT组则给予等剂量无菌生理盐水.股骨远端软骨下骨骨密度和胫骨近端骨组织形态计量学分析,通过关节软骨Mankin评分和MMP-13免疫组化染色观察关节软骨的退变和软骨基质的降解程度.[结果](1)ACLT+NS组股骨内侧髁骨密度显著低于Sham组和ACLT+ALN组(P＜0.05);(2)ACLT+ALN组的胫骨近端骨量显著高于ACLT+NS组(P＜0.05);(3)ACLT+ALN组的关节软骨Mankin评分和MMP-13免疫组化染色平均积分光密度显著低于ACLT+Ns组(P＜0.05).[结论]阿仑膦酸钠20 μg·kg-1·2 d-1皮下注射12周可以预防ACLT大鼠关节软骨退变,其作用机制可能与下调MMP-13的表达和增加软骨下骨骨量有关.     

骨性关节炎中软骨下骨与软骨退变的关系研究进展

目的 综述软骨下骨在骨性关节炎(osteoarthritis,OA)发病中的作用研究进展,展望可能的研究方向. 方法 广泛查阅近年来有关软骨下骨在OA时病理变化的文献,并对生物力学效应、骨重塑、生物学因素等方面进行总结分析. 结果 软骨下骨硬化或软化不仅是OA发生的结果 ,而且与其发生发展密切相关,抑制软骨下骨骨代谢可以延缓关节软骨破坏. 结论 OA治疗既应关注软骨变化,又要预防软骨下骨退变.     

软骨下骨在骨性关节炎发病中的作用研究

长期以来对骨性关节炎（OA）的研究一直集中在关节软骨退变方面，对软骨下骨的研究未得到重视。近年研究发现软骨下骨改变在OA发病过程中起着积极作用，软骨下骨硬化与OA的发生、发展密切相关，不只是OA发生的结果，提示OA治疗有必要兼顾两者，既关注软骨，对软骨下骨退变也要早作预防。该文从软骨下骨的生物力学、影像学、形态计量学、病理学改变等方面就软骨下骨在骨性关节类窟痛中的作用研究井展作一综述。     

软骨下骨重塑在骨关节炎中的作用

<正>骨关节炎(osteoarthritis,OA)是由多种因素引起的复杂性关节退行性疾病。通常认为,OA病理与软骨下骨硬化密切相关,软骨下骨硬化可导致增龄性关节退行性变。近年的研究表明,OA早期常伴有骨重塑加快引起的骨量丢失,晚期可见骨转换率降低并引起软骨下骨板致密化及软骨全部丢失。然而,OA晚期软骨下骨致密化仅见于位于软骨下骨板和钙化软骨,而位于软骨下骨板下方的松质骨骨量明显减     

骨关节炎软骨下骨改变及其作用研究进展

骨关节炎（OA）时软骨下骨结构、生化组成、生物力学及细胞功能均表现异常。OA早期软骨下骨主要表现为骨吸收,晚期主要表现为骨形成。OA软骨下骨异常改变可引发关节疼痛和促进关节软骨退变,抑制或改善软骨下骨异常改变可减轻关节疼痛和延缓软骨退变,软骨下骨靶向治疗有望成为新的治疗手段。该文就OA软骨下骨异常改变及其作用研究进展作一综述。     

降钙素对OA大鼠关节软骨及软骨下骨的保护作用

[目的]研究降钙素(calcitonin,CT)对骨性关节炎(OA)模型大鼠关节软骨和软骨下骨的保护作用.[方法]采用前叉韧带切断(anterior cruciate ligament transection,ACLT)法制备大鼠OA模型,30只12周龄雌性SD大鼠,随机分成3组:假手术组(Sham, n=10)、手术组(ACLT+NS, n=10)和给药组(ACLT+CT, n=10).术后ACLT+CT组皮下注射鲑鱼降钙素10 IU·kg-1·d-1,连续12周;ACLT+NS组则给予等量生理盐水.术后12周处死动物取材,采用Mankin评分系统评分;用双能骨密度仪测量右侧股骨远端1/4骨密度和股骨内外侧髁软骨下骨的骨密度;右侧股骨髁脱钙后切片,行番红"O"染色和MMP-13免疫组化染色;右侧胫骨近端做硬组织切片,测量软骨下松质骨的骨组织形态计量学参数.[结果](1)Sham组和ACLT+CT组关节软骨Mankin评分结果显著低于ACLT+NS组.(2)ACLT+NS组软骨下骨骨密度、骨量(BV/TV,Tb.Th)均显著高于Sham组及ACLT+CT组.(3)ACLT+NS组关节软骨MMP-13表达显著高于Sham组及ACLT+CT.[结论]降钙素10 IU·kg-1·d-1皮下注射12周能够抑制OA大鼠关节软骨的退变,其作用机制可能与下调关节软骨中MMP-13的表达及抑制软骨下骨的增生硬化并改善其微观结构有关.     

Alendronate protects against articular cartilage erosion by inhibiting subchondral bone loss in ovariectomized rats

Osteoporosis (OP) and osteoarthritis (OA) are major health problems in the increasing elderly population, particularly in postmenopausal women, but their relationship remains unclear. The present study investigated whether alendronate (ALN), a potent inhibitor of bone resorption, could protect articular cartilage from degeneration in a combined animal model of OP and OA induced by ovariectomy (OVX). Seventy-eight seven-month-old female Sprague–Dawley rats were assigned into five experimental groups: (1) sham-operated with vehicle treatment, (2) sham-operated with ALN treatment, (3) OVX with vehicle treatment, (4) ALN treatment starting at OVX, and (5) ALN treatment starting at eight weeks after OVX. Histological and micro-CT analyses, together with urine collagen degradation markers, indicated that early ALN treatment completely prevented both subchondral bone loss and cartilage surface erosion induced by OVX. Although late ALN treatment also inhibited subchondral bone loss and significantly reduced cartilage erosion in the OVX rats, these tissues did not completely recover even after 10-weeks of ALN treatment. Quantitative RT-PCR analyses showed that the protective effect of ALN correlated with increased ratio of OPG/RANKL in both subchondral bone and cartilage. Moreover, whereas OVX caused upregulation of expression of matrix metalloproteinases MMP-13 and MMP-9 in the articular cartilage and chondrocytes in the interface between the articular cartilage and subchondral bone, respectively, early ALN treatment blocked whereas late ALN treatment attenuated the upregulation of these catabolic enzymes in the corresponding tissues. Together, these data indicate that the subchondral bone loss plays an important role in OA pathogenesis in the combined OP and OA model and suggest that treatment timing is an important factor for the effectiveness of anti-resorptive drug therapy of combined OP and OA.     

Chondroprotective effect of alendronate in a rabbit model of osteoarthritis

The aim of this study was to determine how alendronate (ALN) alters cartilage degeneration and periarticular bone quality in a rabbit anterior cruciate ligament transection (ACLT) model of osteoarthritis (OA). Thirty rabbits underwent an ACLT on the left knee and a sham operation on the right knee. Fifteen rabbits received weekly subcutaneous injections of ALN (0.14 mg/kg) and 15 rabbits (the control [cont] group) received saline. Animal knees were divided into four groups: cont/sham, cont/ACLT, ALN/sham, and ALN/ACLT. Histological, radiological, and immunohistochemical indices were evaluated for each group. Bone volume ratios by micro‐computed tomography showed that ALN prevented periarticular bone loss. Histologically, the cont/ACLT group had significantly worse cartilage damage than the cont/sham group 12 weeks after the surgery. However, the ALN/ACLT group had mild cartilage degeneration compared with that of the ALN/sham group. Immunohistochemical analysis showed that ALN suppressed the expression of matrix metalloproteinase‐13, interleukin‐1β, type‐X collagen, vascular endothelial growth factor, and receptor activator of nuclear factor κB ligand in OA cartilage. ALN had a chondroprotective effect in an experimental rabbit model of OA. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1572–1577, 2011     

Proposal for a nomenclature for magnetic resonance imaging based measures of articular cartilage in osteoarthritis

OBJECTIVE: Magnetic resonance imaging (MRI) of articular cartilage has evolved to be an important tool in research on cartilage (patho)physiology and osteoarthritis (OA). MRI provides a wealth of novel and quantitative information, but there exists no commonly accepted terminology for reporting these metrics. The objective of this initiative was to propose a nomenclature for definitions and names to be used in scientific communications and to give recommendations as to which minimal methodological information should be provided when reporting MRI-based measures of articular cartilage in OA. METHODS: An international group of experts with direct experience in MRI measurement of cartilage morphology or composition reviewed the existing literature. Through an iterative process that included a meeting with a larger group of scientists and clinicians (December 2nd, 2004, Chicago, IL, USA), they discussed, refined, and proposed a nomenclature for MRI-based measures of articular cartilage in OA. RESULTS: The group proposes a nomenclature that describes: (1) the anatomical location and (2) the structural feature being measured, each name consisting of a metric variable combined with a tissue label. In addition, the group recommends minimal methodological information that should be described. CONCLUSIONS: Utilization of this nomenclature should facilitate communication within the scientific community. Further, the uniform adoption of comprehensive nomenclature to describe quantitative MRI- features of articular cartilage should strengthen epidemiological, clinical, and pharmacological studies in OA.     

Nonsteroidal antiinflammatory drugs in treatment of osteoarthritis

It is clear that some synovial inflammation occurs in joints affected by osteoarthritis (OA) and it is well recognized that many patients with OA experience a decrease in pain and joint stiffness following administration of salicylates or other nonsteroidal antiinflammatory drugs (NSAIDs). However, neither the extent to which synovitis contributes to the cartilage breakdown in OA nor the effects of chronic administration of NSAIDs on the natural history of OA in humans is known. Recent studies indicate that several NSAIDs, including salicylates, suppress proteoglycan synthesis in articular cartilage in vitro. The effect on OA cartilage is more marked than that on normal cartilage. Other studies show that salicylate feeding may suppress proteoglycan metabolism in degenerating cartilage in vivo, aggravating the decrease in proteoglycan content caused by the disease itself. However, no effect of salicylates on normal articular cartilage has been observed in vivo. In damaged cartilage the magnitude of NSAID-induced suppression of proteoglycan metabolism appears to be related inversely to the proteoglycan content of the tissue. In addition, the NSAIDs used in treatment of arthritis today may differ with respect to their in vivo effects on articular cartilage metabolism due, in part, to differences between the molar concentrations of these drugs in synovial fluid.     

Degradation of the cartilage collagen matrix associated with changes in chondrocytes in osteoarthrosis. Assessment by loss of background fluorescence and immunodetection of matrix components.

Articular cartilage damage and eventual loss is the primary pathological change seen in osteoarthrosis (OA). In this study we have investigated the link between turnover of the collagen matrix and changes in chondrocytes. The background fluorescence of articular cartilage, as indicated by its emission spectrum and resistance to extraction was generated by the slow non-enzymic modification of the collagen matrix by advanced glycation end products (AGEs). Assessment of changes in background fluorescence in sections of articular cartilage provided a narrative of collagen degradation. Patients without OA pathology typically had a uniform strong background fluorescence throughout the depth of the cartilage. Cartilage from OA patients showed a range of changes in background fluorescence dependent on depth from the articular surface and proximity to overt lesions. Loss of background fluorescence was centered on chondrocytes, more extensive near the surface and associated with detection of the proteoglycan epitope 7D4. Expression of type X collagen was seen in articular cartilage in the region of the interface of with subchondral bone in most OA patients but was not associated with prominent, pericellular, loss of background fluorescence. These observations are consistent with progressive cartilage damage in OA, whereby collagen turnover and loss of surface integrity is associated with chondrocyte activity similar to that seen in immature articular cartilage.     

The current progress in understanding the molecular functions and mechanisms of visfatin in osteoarthritis

Osteoarthritis, (OA), also known as degenerative arthritis or degenerative joint disease, is the most common form of arthritis, affecting millions of people worldwide. It is a group of mechanical abnormalities involving degradation of the joints and occurs when the protective cartilage (articular cartilage) on the ends of bones such as the knees, hips and fingers abrades over time. It mainly affects the whole joint structure, including the articular cartilage, subchondral bone and synovial tissue. Extensive work has been done in the past decades to investigate the cellular mechanism of this disease. However, to date, it is still poorly understood, and there is no effective treatment. Recently, both in vitro and in vivo studies have confirmed adipokines play critical roles during OA development. Among these, leptin and adiponectin have been well investigated, whereas the effect of the novel adipokine, visfatin, on OA still needs to be revealed. Therefore, in this short review, we will focus on visfatin and summarize the current progress in the research on its role in OA development.     

Selective COX-2 inhibition is favorable to human early and late-stage osteoarthritic cartilage: a human in vitro study

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of osteoarthritis (OA). For the outcome of treatment the direct effects of NSAIDs on cartilage may be more important than indirect effects on inflammation, considered being secondary in OA. For clinical practice, it is relevant to study effects of NSAIDs on early stages of OA. Therefore we studied the direct effects of celecoxib on human degenerated OA cartilage and compared the effects with those on human healthy cartilage and human end-stage OA cartilage. METHODS: Degenerated, late-stage OA, and healthy human articular cartilage were exposed (7 days of culture) to celecoxib (0.1-10 microM). Changes in cartilage proteoglycan turnover (synthesis, retention, and release), proteoglycan content, prostaglandin E2 (PGE2) and nitric oxide (NO) production were determined. RESULTS: Both degenerated and established OA cartilage showed its characteristic changes in proteoglycan turnover (all P<0.05). Celecoxib at 1 microM was able to increase synthesis of degenerated cartilage and normalize both releases of newly formed and resident proteoglycans. Importantly, 1 microM celecoxib influenced matrix integrity by enhancing proteoglycan content. Similar results were found for end-stage OA cartilage. Enhanced PGE2 production in degenerative and OA cartilage could be decreased by celecoxib, whereas no effect on enhanced NO production was found. No significant effects of celecoxib on normal cartilage were found. DISCUSSION: Celecoxib, in a clinical relevant concentration, showed in vitro a significant beneficial effect, not only on late-stage OA but also on more early stages of OA, whereas healthy cartilage remained unaffected, suggesting chondroprotective properties of celecoxib in the treatment of degenerative joint disorders.     

Premature osteoarthritis in the Disproportionate micromelia (Dmm) mouse

OBJECTIVE: Degeneration of articular cartilage leads to the development of osteoarthritis (OA), but the molecular pathology of the disease is poorly understood. The Disproportionate micromelia (Dmm) mouse has a deletion mutation in the C-propeptide encoding region of Col2a1, which leads to a defective cartilage matrix. The objective of this study was to determine whether heterozygous (Dmm/+) mice develop premature OA, and could therefore serve as an animal model for studying the molecular pathways leading to OA. DESIGN: Histological analysis was utilized to determine the state of articular cartilage degeneration in Dmm/+ mice at 3, 6, 9, 12, 15, and 22 months of age. Severity of OA was quantified with a modified Mankin scoring system. In addition, articular cartilage thickness, cell density, and the extracellular matrix (ECM) fraction of articular cartilage were quantified. RESULTS: Articular cartilage erosion was significantly more severe in Dmm/+ than in wild-type (+/+) mice beginning at 9 months, and modified Mankin scoring revealed Dmm/+ articular cartilage to be in a more severe osteoarthritic state as early as 3 months. In addition, Dmm/+ articular cartilage was thinner than +/+ cartilage and showed increased cell density and decreased matrix fraction compared with +/+ from the earliest time points measured. CONCLUSIONS: The present study demonstrates that Dmm/+ mice develop premature OA. The observed degenerative changes of Dmm/+ articular cartilage closely resemble those of human OA patients, with or without Col2a1 mutations, suggesting that Dmm/+ mice are a useful model for investigating mechanisms involved in OA.     

Macro view of microRNA function in osteoarthritis

Osteoarthritis (OA), the most common musculoskeletal disorder, is complex, multifaceted, and characterized by degradation of articular cartilage and alterations in other joint tissues. Although some pathogenic pathways have been characterized, current knowledge is incomplete and effective approaches to the prevention or treatment of OA are lacking. Understanding novel molecular mechanisms that are involved in the maintenance and destruction of articular cartilage, including extracellular regulators and intracellular signalling mechanisms in joint cells that control cartilage homeostasis, has the potential to identify new therapeutic targets in OA. MicroRNAs control tissue development and homeostasis by fine-tuning gene expression, with expression patterns specific to tissues and developmental stages, and are increasingly implicated in the pathogenesis of complex diseases such as cancer and cardiovascular disorders. The emergent roles of microRNAs in cartilage homeostasis and OA pathogenesis are summarized in this Review, alongside potential clinical applications.     

A review of the differences between normal and osteoarthritis articular cartilage in human knee and ankle joints

BackgroundOsteoarthritis (OA) is the most common joint disease yet its pathophysiology is still poorly understood. It is more prevalent in some lower limb joints than others; in particular the knee is more commonly affected than the ankle. Research into articular cartilage and OA has primarily focussed on using animal models. However, it is apparent that articular cartilage differs between species, so more research is concentrating on human cartilage.ObjectiveThis paper reviews recent studies that have been undertaken to elucidate the reasons for this, and to discover if the findings would alter the conception that articular cartilage is not capable of repair.MethodPrimary research papers into human knee and ankle cartilage published since 1997 have been reviewed.ResultsDifferences in the structure, metabolism, physical properties and response to trauma have been found, implying that ankle cartilage may be more resistant to damage.ConclusionsMore research is needed before definitive conclusions can be reached, but the findings so far suggest that OA should not be accepted as the inevitable outcome of joint injury and individuals and practitioners, such as podiatrists, may be able to use simple measures to prevent or delay its onset.