软骨下骨与骨性关节炎病变的发生发展:从基础研究到临床治疗

骨性关节炎(OA)是软骨与骨的退行性变过程。软骨下骨是构成关节结构和功能的基本单位之一,维持软骨正常结构和功能。在复杂应力和生物学作用下,OA软骨下骨的重塑和结构改变使软骨承受更高的应力。软骨下骨内血管生成和结构病变扩大了骨软骨异常交流途径,软骨下骨产生的代谢调节因子通过异常生物学交流直接促进软骨退变。研究软骨下骨内细胞及其变化,血管生成与骨软骨间生物学交流,揭示软骨下骨重塑和结构变化特点,探寻改善骨重塑治疗方法,将有利于延缓OA病变进展,有效防治OA。     

软骨下骨与骨性关节炎病变的发生发展：从基础研究到临床治疗

骨性关节炎（OA）是软骨与骨的退行性变过程。软骨下骨是构成关节结构和功能的基本单位之一,维持软骨正常结构和功能。在复杂应力和生物学作用下,OA软骨下骨的重塑和结构改变使软骨承受更高的应力。软骨下骨内血管生成和结构病变扩大了骨软骨异常交流途径,软骨下骨产生的代谢调节因子通过异常生物学交流直接促进软骨退变。研究软骨下骨内细胞及其变化,血管生成与骨软骨间生物学交流,揭示软骨下骨重塑和结构变化特点,探寻改善骨重塑治疗方法,将有利于延缓OA病变进展,有效防治OA。     

骨性关节炎软骨和软骨下骨之间信号通路

骨性关节炎(osteoarthritis,OA)的发生和发展离不开软骨和软骨下骨共同病变的过程。信号通路的异常在调控OA软骨下骨和软骨的病变中起重要作用。Wnt、转化生长因子β(transforming growth factorβ,TGFβ)/骨形态发生蛋白(bone morphogenetic protein,BMP)、丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)信号通路对骨和软骨正常生长发育和代谢有着重要的调控作用,维持了关节的健康和平衡。研究显示,在OA中,这些信号通路的改变不仅可使OA软骨下骨和软骨的细胞表型和分子功能失衡,细胞外基质的合成破坏,软骨下骨骨重塑,还可通过破坏组织细胞的代谢进一步改变骨和软骨的结构及应力承担能力。因此,本文围绕骨关节炎病变中Wnt、TGFβ/BMP、MAPK信号交流在OA中软骨下骨和软骨病变中的作用和机制进行综述,以期为OA和其他骨关节疾病的研究和治疗提供新的方法和思路。     

膝关节镜下大骨节病与骨性关节炎的病理形态对照分析

目的 通过膝关节镜将大骨节病与骨性关节炎病变形态进行对照，以便膝关节镜下对大骨节病的诊断和选择治疗方法。方法 采用膝关节清理术，于膝关节手术中镜下观察滑膜、髌骨、股骨、胫骨及半月板改变。结果 大骨节病患者膝关节的滑膜、软骨、半月板损伤重且改变明显，与骨性关节炎比较差异有显著意义。结论 尽管大骨节病发展的结局也是骨性关节炎，但其病理形态与骨性关节炎仍有差别，手术中要充分考虑大片软骨剥离的特殊性。     

脂肪组织对骨代谢的调节关系

骨代谢的调节是一个复杂的过程,其本质是调节成骨细胞和破骨细胞的活动。通过破骨细胞吸收旧骨和成骨细胞形成新骨这两个相互偶联又相互制约的骨转换过程,骨组织不断地进行骨重建,以对自身进行新陈代谢~([1])。成骨细胞分泌核转录因子(NF)-κB受体活化因子配体(RANKL),破骨细胞分泌NF-κB受体活化因子(RANK)。RANKL与RANK结合后,传递信号,激活NF-κB,从而促进破骨细胞增     

老年骨性关节炎与关节软骨酶降解

骨性关节炎是老年人常见的关节退行性疾病,近年来通过动物实验及临床研究,发现骨性关节炎关节软骨的破坏与软骨中或滑膜中中性蛋白酶及胶元酶降解软骨中的主要成份有关。对实验动物给予酶拮抗剂能显著减轻实验动物关节软骨的破坏,如果通过进一步研究应用于临床,将为治疗及预防骨性关节炎这一顽疾开辟一个新的途径。     

过量氟对实验大鼠软骨代谢的影响

近年来,氟骨症的发病机制研究已经取得了较大的进展。李广生等成功地用大白鼠复制了骨软化型氟骨症,证实了过量氟对软骨组织有明显的形态学损害。生长板软骨与骨组织相接,直接控制骨的生长、发育。但是有关过量氟对软骨代谢影响的报道较少。本文报道了低营养偏食饲料和过量氟对实验大鼠软骨代谢的影响。     

Notch信号通路与骨发生和骨重建

Notch信号通路对调节胚胎细胞和成体细胞增生、分化、凋亡以及前体细胞的自我更新具有重要意义。它可通过协调胚胎期生长板内软骨细胞分化和生长,控制骨组织正常发生。骨重建是对病损骨组织的再生和修复,主要由成骨细胞和破骨细胞参与,Notch信号除可对上述2种细胞增生、分化、成熟等进行调控外,也可介导依赖于成骨细胞的破骨细胞生成。本文试以Notch信号对软骨细胞、成骨细胞、破骨细胞等细胞学行为改变为主线,探讨Notch信号对上述2种骨生物学行为调节的作用机制。     

趋化因子受体CXCR1/2及其配体在骨代谢中的作用

骨组织稳态受成骨细胞与破骨细胞之间的动态平衡所调节,在RA及骨转移瘤等病理状态下,多种细胞因子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进而导致骨破坏。趋化因子在骨破坏过程中发挥着举足轻重的作用,其中含有ELR（Glu-Leu-Arg）结构域的CXC趋化因子可与CXCR1或CXCR2结合,参与破骨细胞活化...     

膝骨性关节炎患者胫骨软骨和软骨下骨ERK1/2信号蛋白表达

目的观察膝骨性关节炎(osteoarthritis,OA)患者胫骨平台硬化区与非硬化区软骨和软骨下骨细胞外调节蛋白激酶(extracellular signal-regulated kinase 1/2,ERK1/2)信号蛋白的改变,探讨OA的发病机制。方法收集OA患者行全膝关节置换术后遗弃的胫骨平台组织(n=22),大体观察后,通过硬组织甲苯胺蓝染色证实并区分硬化与非硬化区软骨和软骨下骨观察病理结构改变,分离硬化与非硬化区的软骨与软骨下骨组织,通过Western blot法分别测定硬化区(n=22)与非硬化区(n=18)软骨及软骨下骨ERK1/2总蛋白以及磷酸化蛋白的表达。结果 OA患者膝关节胫骨平台硬组织甲苯胺蓝染色观察显示,硬化区软骨层变薄、纤维化、局部可有断裂,形成深达软骨下骨的微裂隙,软骨细胞减少且层次不清排列欠佳,软骨下骨骨小梁厚度增加。OA胫骨平台硬化区的软骨及软骨下骨分别与非硬化区相比ERK1/2总蛋白表达量无明显差异(t=1. 92,P=0. 062; t=1. 75,P=0. 088),但硬化区软骨及软骨下骨ERK1/2磷酸化蛋白分别明显高于非硬化区,差异有统计学意义(t=15. 04,P0. 001; t=20. 37,P0. 001)。结论 OA硬化区软骨和软骨下骨ERK1/2信号蛋白不同于非硬化区,硬化区软骨和软骨下骨ERK1/2蛋白磷酸化增强可能是其微结构病变的重要原因之一。     

Microfractures and microcracks in subchondral bone: are they relevant to osteoarthrosis?

The existing data are consistent with the view that reactivation of the secondary center of ossification and not the stiffening of the metaphyseal trabecular bone is a mechanism of cartilage loss in idiopathic OA. The stiffening of the subchondral calcified structures would appear to be etiologically incidental and, as the arthrotic process progresses, sometimes locally transient. It is also now clear that although the apparent density of the subchondral cortical plate increases because of thickening of the plate as the OA process progresses, the elastic modulus of the bone might be reduced locally because of increases in vascularization and in the rate of bony remodeling subjacent to the cartilage. Microcracks in the subchondral mineralized tissues might contribute to degeneration of the hyaline cartilage by initiating vascular invasion of the calcified cartilage, leading to reactivation of the tidemark and enchondral ossification with subsequent thinning of the overlying articular cartilage. The thinning would tend to increase shear stresses at the base of the articular cartilage [38], overwhelming the ability of the cartilage to repair itself, resulting in cartilage degeneration. The pathogenesis of cartilage breakdown in OA is a biological and a mechanical process. OA can be understood only if the relationship between the mechanics and the biology is fully appreciated. Failure to properly absorb impact leads to microdamage in the subchondral plate and calcified cartilage. The authors believe that this action causes the secondary center of ossification at the tidemark to advance by enchondral ossification, leading to thickening of the mineralized tissues and thinning of the overlying hyaline articular cartilage. Microcracks will cause the initiation of targeted remodeling, accounting for the increased turnover and reduced material density of the subchondral plate. The resultant thinning of the articular cartilage might lead to initiation of further microdamage in bone and cartilage through a positive feedback mechanism, which can ultimately lead to complete loss of the articular cartilage. In this view, the mechanical overload that initiates microdamage of the subchondral bone provokes a biological response that potentiates the progression of articular cartilage damage in OA.     

Subchondral bone sclerosis in osteoarthritis: not just an innocent bystander

Abstract

?Osteoarthritis (OA) is considered to be a complex illness in which the tissues of the joint play a significant role in the initiation and/or progression of the pathophysiology. We still do not completely understand what initiates the degradation and loss of cartilage. However, it has been suggested that increased catabolism due to elevated cytokines and growth factors in OA joints plays a significant role. Recent evidence suggests a key role for the subchondral bone tissue in the progression and/or initiation of OA. Indeed, the subchondral bone tissue produces a number of similar proinflammatory cytokines, and growth factors are involved in cartilage tissue remodeling. Interestingly, studies have shown the presence of clefts or channels in the tidemark that appears early in OA, indicating a possible way to traffic cytokines and growth factors from the subchondral compartment to the overlying cartilage. Therefore, it is possible that certain bone-derived products drive cartilage metabolism. Potential candidates include insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β) interleukin 1β (IL-1β), and interleukin-6 (IL-6). Demonstrating that the subchondral bone plays a role in the initiation of OA would greatly contribute to furthering our knowledge of this pathology and provide new insights for therapeutic approaches.     

Vascular pathology and osteoarthritis

There is mounting evidence that vascular pathology plays a role in the initiation and/or progression of the major disease of joints: osteoarthritis (OA). Potential mechanisms are: episodically reduced blood flow through the small vessels in the subchondral bone at the ends of long bones, and related to this, reduced interstitial fluid flow in subchondral bone. Blood flow may be reduced by venous occlusion and stasis or by the development of microemboli in the subchondral vessels. There are several likely effects of subchondral ischaemia: the first of these is compromised nutrient and gas exchange into the articular cartilage, a potential initiator of degradative changes in the cartilage. The second is apoptosis of osteocytes in regions of the subchondral bone, which would initiate osteoclastic resorption of that bone and at least temporarily reduce the bony support for the overlying cartilage. It may be important to recognize these potential aetiological factors in order to develop more effective treatments to inhibit the progression of OA.     

Osteocalcin synthesis by human osteoblasts from normal and osteoarthritic bone after vitamin D<Subscript>3</Subscript> stimulation

Alterations in osteoblast metabolism are involved in the pathogenesis of typical subchondral bone changes in osteoarthritis (OA). Osteocalcin is a specific bone protein, synthesised by the osteoblasts, which can be considered a marker of metabolic activity of these cells. In this study we correlated osteocalcin production from human osteoblasts isolated from healthy and osteoarthritic subjects to the degree of cartilage damage, before and after stimulation with 1,25(OH)₂-vitamin D_3, the active metabolite of vitamin D₃. We isolated human osteoblasts from cancellous bone of healthy subjects and from subchondral bone of osteoarthritic subjects and considered the osteoblasts corresponding to different degrees of cartilage damage as different cell populations. We determined the osteocalcin production in normal and osteoarthritic osteoblasts from maximal and minimal cartilage damage areas both under basal conditions and after vitamin D₃ stimulation. Compared to normal osteoblasts, under basal conditions osteocalcin production is significantly greater in osteoarthritic osteoblasts, corresponding both to maximal and minimal damage joint areas. No differences were observed between osteoblasts from maximal and minimal damage areas. The response of osteoblasts to vitamin D₃ stimulation appeared to be proportional to the degree of joint damage, as the vitamin D₃-induced increase in osteocalcin is proportionally greater in maximally damaged osteoblasts compared to minimally damaged ones. Thus, after vitamin D₃ stimulation, a significant increase in osteocalcin production by maximally damaged osteoblasts compared to the minimally damaged ones was observed. This study confirms abnormal osteoarthritic osteoblast behaviour and indicates that osteoblasts from different areas of the same affected joint may be metabolically different, supporting the hypothesis that subchondral osteoblasts may play an essential role in the pathogenesis of OA.     

Subchondral bone sclerosis in osteoarthritis: not just an innocent bystander

 Osteoarthritis (OA) is considered to be a complex illness in which the tissues of the joint play a significant role in the initiation and/or progression of the pathophysiology. We still do not completely understand what initiates the degradation and loss of cartilage. However, it has been suggested that increased catabolism due to elevated cytokines and growth factors in OA joints plays a significant role. Recent evidence suggests a key role for the subchondral bone tissue in the progression and/or initiation of OA. Indeed, the subchondral bone tissue produces a number of similar proinflammatory cytokines, and growth factors are involved in cartilage tissue remodeling. Interestingly, studies have shown the presence of clefts or channels in the tidemark that appears early in OA, indicating a possible way to traffic cytokines and growth factors from the subchondral compartment to the overlying cartilage. Therefore, it is possible that certain bone-derived products drive cartilage metabolism. Potential candidates include insulin-like growth factor-1 (IGF-1), transforming growth factor-β (TGF-β) interleukin 1β (IL-1β), and interleukin-6 (IL-6). Demonstrating that the subchondral bone plays a role in the initiation of OA would greatly contribute to furthering our knowledge of this pathology and provide new insights for therapeutic approaches. Acknowledgments The Arthritis Society of Canada grant No. 98043 and the Fonds De la Recherche en Santé du Québec (FRSQ) “équipe Prioritaire” supported this research. Correspondence to:D. Lajeunesse     

Role of eicosanoids in structural degradation in osteoarthritis

PURPOSE OF REVIEW: Osteoarthritis is characterized mainly by degenerative changes in joint cartilage, ultimately resulting in loss of cartilage, and alterations in the subchondral bone. Osteoarthritis osteoblasts show a number of metabolic alterations that may interfere with normal cell metabolism and signaling, possibly leading to altered extracellular matrix composition. This review examines the role of eicosanoids in this structural degradation. RECENT FINDINGS: Prostaglandins exert diverse modulatory roles in osteoarthritis, with prostaglandin E2 known to play an important role in inflammation. Prostaglandins and leukotriene B4 have been shown to regulate proinflammatory cytokine and interstitial collagenase synthesis in human osteoarthritis synovial membrane explants. Human osteoarthritis osteoblasts produce variable levels of prostaglandin E2 and leukotriene B4 compared with normal osteoblasts. Prostaglandin E2 levels can distinguish two types of patients with osteoarthritis: osteoblasts from one group produce low levels of prostaglandin E2 and interleukin-6, and the other shows an increase in production. In contrast, osteoarthritis osteoblasts that produce high levels of prostaglandin E2 produce low levels of leukotriene B4 and vice versa. This observation could be explained by the selective metabolism of arachidonic acid via the 5-lipoxygenase or cyclooxygenase pathways in osteoarthritis osteoblasts. SUMMARY: Prostaglandins play a significant role not only in joint physiology, but also in the pathogenesis of joint disorders. In addition, it has been identified that osteoarthritis subchondral osteoblasts can synthesize leukotriene B4, indicating a role of leukotrienes in bone remodeling associated with osteoarthritis. A therapeutic intervention that blocks lipoxygenase/cyclooxygenase pathways, thereby inhibiting production of prostaglandins and leukotrienes, may therefore be very attractive for the treatment of osteoarthritis patients.     

Carprofen simultaneously reduces progression of morphological changes in cartilage and subchondral bone in experimental dog osteoarthritis

OBJECTIVE: To examine the effect of a nonsteroidal antiinflammatory drug, carprofen, on the structure and metabolism of cartilage and subchondral bone in the experimental osteoarthritic (OA) canine model. METHODS: Experimental Groups 1 and 2 received a sectioning of the anterior cruciate ligament (ACL) of the right stifle joint, and were administered carprofen (2.2 and 4.4 mg/kg/twice daily/po, respectively) for 8 weeks beginning 4 weeks postsurgery. Group 3 received ACL sectioning and no treatment. Group 4 was composed of unoperated normal dogs. Cartilage macroscopic lesions were assessed, and their histological severity was graded. Specimens of subchondral bones were fixed, decalcified, and stained with hematoxylin/eosin. The level of metalloprotease (MMP) activity in cartilage was measured. Osteoblast cells were prepared from the subchondral bone. The level of synthesis of osteoblast biomarkers (osteocalcin, alkaline phosphatase), as well as urokinase plasminogen activator (uPA) activity and insulin-like growth factor (IGF-1) in the culture medium, was estimated. RESULTS: Carprofen treatment decreased the width of osteophytes (p < 0.01), the size of cartilage lesions, and the histologic severity of cartilage lesions (p < 0.008). There was no difference in the levels of MMP activity in cartilage between OA and carprofen treated groups. In OA dogs, the subchondral bone plate was thinner and was the site of an extensive remodeling process with numerous lacunae. Dogs treated with carprofen showed a marked decrease in the remodeling activity with normal plate thickness, and subchondral bone morphology resembling that of normal dogs. Osteoblasts from untreated OA dogs showed slightly higher alkaline phosphatase activities and osteocalcin release that reverted back to normal upon carprofen treatment. Moreover, uPA activity and IGF-1 levels were increased in OA dogs and were significantly reduced in carprofen treated dogs. CONCLUSION: Under therapeutic conditions, treatment with carprofen could reduce the progression of early structural changes in experimental OA. Carprofen treatment also delays and/or prevents the abnormal metabolism of subchondral osteoblasts in this model. The hypothesis of a possible link between the protective effect of carprofen and its effect on subchondral bone is of interest in the context of therapeutic intervention.     

Subchondral bone in osteoarthritis: a biologic link with articular cartilage leading to abnormal remodeling

PURPOSE OF REVIEW: This review deals with new findings highlighting the concept of cross-talk between subchondral bone tissue and articular cartilage that may be crucial for the initiation and/or progression of osteoarthritis. In this review, new factors either produced by subchondral bone tissue or modifying osteoblast metabolism, yet implicated in osteoarthritis, are discussed. RECENT FINDINGS: The development of cartilage degeneration is concomitant with subchondral bone thickness in osteoarthritis, whereas it is related to higher subchondral bone activity and dysregulation in the synthesis of bone proteins. As an immediate consequence, homotrimers of type 1 collagen are formed that could lead to undermineralization of this tissue. This dysregulation also leads to abnormal production of different factors by osteoblasts such as prostaglandins, leukotrienes, and growth factors. Because microcracks or neovascularization provide a link between the subchondral bone tissue and articular cartilage, these factors could contribute to the abnormal remodeling of osteoarthritic cartilage. SUMMARY: These findings have an immediate implication for research because new tools need to be developed to study the subchondral bone-cartilage functional unit. Moreover, it could lead to a possible cure for osteoarthritis because this pathology should be considered both a bone and cartilage disease.     

Role of subchondral bone in osteoarthritis development: a comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis

OBJECTIVE: To evaluate the relationships among cartilage and subchondral bone before and after the onset of cartilage degeneration in the Hartley guinea pig model of spontaneous osteoarthritis (OA) as compared with those in Weiser-Maple guinea pigs, which do not develop OA. METHODS: Mice from each strain were used at ages 2, 3, 5, and 8 months (n = 7 at each time point). The region observed was the medial tibial plateau. Cartilage degeneration was evaluated histologically. Subchondral bone structure was evaluated based on subchondral bone plate thickness and subchondral cancellous bone trabecular parameters calculated from the microfocal computed tomography 3-dimensional reconstruction image. The bone mineral density (BMD) of the subchondral cancellous bone as well as levels of urinary N-telopeptide of type I collagen (NTX) and serum osteocalcin (OC) were measured. RESULTS: In Hartley guinea pigs, the number of chondrocytes in the surface layer started to decrease at 3 months. At 8 months, fibrillation expanded to the radial zone. In Weiser-Maple guinea pigs, no cartilage degeneration was noted even at 8 months. Subchondral bone plate thickness was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The subchondral bone had a rod-like and convex structure at 2 months in Hartley guinea pigs. BMD was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The serum OC level was significantly higher in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months and 3 months, whereas the urinary NTX level was significantly lower in Hartley guinea pigs at 3 months. CONCLUSION: Subchondral bone is fragile, and bone formation may be promoted in subchondral bone before the onset of cartilage degeneration in Hartley guinea pigs. Subchondral bone may be involved in the development of OA.