Search

Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO) model of OA. For this purpose, OA was induced by surgical knee destabilization in wild-type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n = 10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1 beta as an inflammatory insult. Our results showed that tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM-EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. We found that hypertrophic—IHH—and inflammatory—COX-2—markers co-localized in OA cartilage samples. We concluded that tamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM-EvccKO mice, but it did not ameliorate cartilage damage. Overall, our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA., This work was financially supported by grants from the Instituto de Salud Carlos III [PI20/00349, PI16/00065, PI18/00261] and Fondo Europeo de Desarrollo Regional (FEDER); and by the Spanish Ministry of Science and Innovatin (MICINN) [SAF-2013-43365-R and SAF2016-75434-R] to VLR-P. AL and PG were funded by Fundación Conchita Rábago.

BackgroundChondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO) model of OA.MethodsOA was induced by surgical knee destabilization in wild-type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n=10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1β as an inflammatory insult.ResultsTamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM-EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. Hypertrophic – IHH – and inflammatory – COX-2 – markers co-localized in OA cartilage samples.ConclusionsTamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM-EvccKO mice, but it did not ameliorate cartilage damage. Our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.

Copyright © 2021 Mobasheri, Fonseca, Gualillo, Henrotin, Largo, Herrero-Beaumont and Rocha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., Osteoarthritis (OA) is the most common form of arthritis affecting more than 500 million people globally. It accounts for more pain and functional disability than any other musculoskeletal disease and is an important source of high societal and economic costs. Although the pathophysiology of OA is poorly understood, the risk factors associated with disease development are well-established. They include age, obesity, sex, previous incidence of joint injuries, meniscal damage, joint instability, malalignment, genetics, bone shape (including anatomical deformities), muscle weakness and sarcopenia, and metabolic disease. Although OA can affect any synovial joint, including joints in the hand, according to studies on the global burden of disease in 2010 and 2017, knee OA represents the greatest societal burden.

Summary Objective We aimed to assess whether an increase in chondrocyte size might be a feature of the articular cartilage (AC) hypertrophic-like phenotype both in experimental and in human osteoarthritis (OA). The anatomical location of these enlarged cells in the cartilage layers was also evaluated. Methods Experimental OA was carried out in female rabbits alone or in combination with osteoporosis (OPOA). The rabbits were subjected to destabilization knee surgery to develop OA. Osteoporosis was induced with ovariectomy and methylprednisolone administration. Human OA samples obtained from knee replacement surgery were also studied. Cartilage lesions and chondrocyte size were assessed in AC sections. Immunostaining of type-X collagen and metalloproteinase-13 were used as markers of the AC hypertrophic transformation. Both the cell size and the gene expression of type-X collagen were further analyzed in primary murine chondrocyte cultures. Results Compared to healthy AC, chondrocyte size was increased both in experimental and in human OA, in correlation with the severity of cartilage damage. No differences in chondrocyte size were found between deeper or more superficial regions of AC. In cell cultures, accretion of hypertrophic markers and cell enlargement were found to occur synchronized. Conclusions We observed an enhancement in the mean size of chondrocytes at the OA cartilage, which showed correlation with cartilage damage, both in human and in experimental OA. The enlarged chondrocytes were homogeneously distributed throughout the AC. Our results suggest that chondrocyte size could be a reliable measure of disease progression, of potential use in the histopathological assessment of OA cartilage.

Extracellular adenosine triphosphate (ATP) plays a central role in a wide variety of joint diseases. ATP is generated intracellularly, and the concentration of the extracellular ATP pool is determined by the regulation of its transport out of the cell. A variety of ATP transporters have been described, with connexins and pannexins the most commonly cited. Both form intercellular channels, known as gap junctions, that facilitate the transport of various small molecules between cells and mediate cell–cell communication. Connexins and pannexins also form pores, or hemichannels, that are permeable to certain molecules, including ATP. All joint tissues express one or more connexins and pannexins, and their expression is altered in some pathological conditions, such as osteoarthritis (OA) and rheumatoid arthritis (RA), indicating that they may be involved in the onset and progression of these pathologies. The aging of the global population, along with increases in the prevalence of obesity and metabolic dysfunction, is associated with a rising frequency of joint diseases along with the increased costs and burden of related illness. The modulation of connexins and pannexins represents an attractive therapeutic target in joint disease, but their complex regulation, their combination of gap-junction-dependent and -independent functions, and their interplay between gap junction and hemichannel formation are not yet fully elucidated. In this review, we try to shed light on the regulation of these proteins and their roles in ATP transport to the extracellular space in the context of joint disease, and specifically OA and RA.

ObjectiveTo evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard.MethodsConsecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0–3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other’s findings.Results11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%—sensitivity of 91% (range 71%–87% in single sites) and specificity of 59% (range 68%–92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation.ConclusionUltrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

We have read with interest the comment from Angelides and Manolios in which they propose an alternative way to account for the potential mechanism of action of glucosamine in osteoarthritis (OA) and other chronic inflammatory diseases.1 Recent and robust epidemiological data suggest that sustained glucosamine intake could partially prevent cardiovascular disease and cancer.2 Our editorial made some hypothetical considerations about the mechanism of action of this compound.3 The editorial also commented on the difficulty of detecting a beneficial effect of glucosamine in OA, due to the modesty of the therapeutic effect, as well as the weakness of the methodological tools employed in OA clinical trials.3 In some way, the relationship between glucosamine and OA takes us fully into the pathophysiology that revolves around immunometabolic regulation, a driver that can account for tissue deterioration in various chronic diseases and still with many aspects to …

Osteoarthritis (OA) is an evolving chronic joint disease with a huge global impact. Given the intricate nature of the etiopathogenesis and subsequent high heterogeneity in the clinical course of OA, it is crucial to discriminate between etiopathogenic endotypes and clinical phenotypes, especially in the early stages of the disease. In this sense, we propose that an OA phenotype should be properly assessed with a set of outcome measures including those specifically related to the main underlying pathophysiological mechanisms. Thus, each OA phenotype can be related to different and clinically meaningful outcomes. OA phenotyping would lead to an adequate patient stratification in well-designed clinical trials and the discovery of precise therapeutic approaches. A significant effort will be required in this field in light of inconclusive results of clinical trials of tissue-targeting agents for the treatment of OA.

Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.

Osteoarthritis (OA) is a disease with a very long course and varied clinical expression in the initial stages, when it is really challenging to adequately measure disease outcomes both in clinical trials and in daily life.1 It is also very difficult to accurately study the efficacy of symptomatic slow-acting drugs for OA and that of non-pharmacological treatments.2 Although the efficacy of glucosamine (GlcN) in the treatment of OA is still a controversial issue3 4, recent high-quality epidemiological studies confirm previous data showing that prolonged GlcN intake, regardless of its effect on OA progression, could decrease cardiovascular disease (CVD) events, and the incidence of CVD-associated diseases.5–8 These data should be analysed keeping in mind that CVD is the main cause of death in patients with OA.9 Different authors suggest that this protective effect may be associated with the anti-inflammatory properties of GlcN,5 although the molecular basis has been only partially defined. The imbalance between the mechanical loading and its absorption by the articular cartilage is the origin of joint tissue alteration in OA. While a severe overload can deteriorate any kind of cartilage, a certain load that is physiologically well tolerated by a robust cartilage could be the origin of pathological alterations for a weakened one.9 Cartilage damage begins when the load prevails over the resistance, which in the midterm activates innate immune response in the different joint tissues, and is, at least partially, responsible for joint deterioration. Unbalanced mechanical forces and damage-associated molecular patterns turn on the innate immune system through the activation of the Toll-like receptors. Once this response is activated, a secondary wave of inflammatory mediators is released, with a robust increase in the concentration of cytokines and metalloproteases, the final effectors of cartilage destruction.9 Certainly, these mediators can …

Osteoarthritis (OA) is a multifactorial joint disease mainly affecting articular cartilage (AC) with a relevant biomechanical component. During endochondral ossification growth plate (GP) chondrocytes arrange in columns. GPs do not ossify in skeletally mature rodents. In neonatal mice, an altered joint loading induces GP chondrocyte disorganization. We aimed to study whether experimental OA involves GP disorganization in adult mice and to assess if it may have additional detrimental effects on AC damage. Knee OA was induced by destabilization of the medial meniscus (DMM) in wild-type (WT) adult mice, and in Tamoxifen-inducible Ellis-van-Creveld syndrome protein (Evc) knockouts (EvccKO), used as a model of GP disorganization due to Hedgehog signalling disruption. Chondrocyte column arrangement was assessed in the tibial GP and expressed as Column Index (CI). Both DMM-operated WT mice and non-operated-EvccKO showed a decreased CI, indicating GP chondrocyte column disarrangement, although in the latter, it was not associated to AC damage. The most severe GP chondrocyte disorganization occurred in DMM-EvccKO mice, in comparison to the other groups. However, this altered GP structure in DMM-EvccKO mice did not exacerbate AC damage. Further studies are needed to confirm the lack of interference of GP alterations on the analysis of AC employing OA mice., This work was financially supported by grants from the Instituto de Salud Carlos III [PI15/00340, PI16/00065, PI18/00261] to RL and GH-B, and Fondo Europeo de Desarrollo Regional (FEDER) by grants SAF-2013–43365-R and SAF2016-75434-R to VL R-P. AL and PG were funded by Fundación Conchita Rábago.

Background Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, although both subchondral bone deterioration and synovial inflammation are also hallmarks of the disease. Chiropractic manipulation (CM) is a therapeutic approach focused on the diagnosis, treatment and prevention of musculoskeletal disorders. It is essentially manual, allowing the chiropractor to restore the normal range of motion and function of the joints, muscles, and ligaments. Clinical evidences suggest that CM might exert positive effects in OA patients. Objectives The aim of this study was to evaluate the effects of CM on cartilage, subchondral bone and synovitis state in an OA rabbit model. Methods Ten (4 months old) male New Zealand rabbits underwent knee surgery to induce OA by transection of anterior cruciate ligament. One week after the surgery, CM was performed using the chiropractic adjusting instrument ActivatorV as follows: Force 2 setting was applied onto the tibial tubercle of the right hind limb (true manipulation, TM-OA group), at an angle of approximately 90°, from medial to lateral, whereas the corresponding left hind limb received a false manipulation (FM-OA group) consisting of ActivatorV firing in the air and slightly touching the tibial tubercle. These procedures were repeated 3 times a week for 8 weeks. Three healthy animals were used as control. Following sacrifice, μCT and histological damage evaluation (Mankin score) were done in femur and tibiae. RANKL/OPG protein expressions were studied by immunohistochemistry in tibia samples. Sinovitis was assessed by Krenn score and immunohistochemistry for macrophages (RAM11) and angiogenesis (CD31) were done. Protein expression of VEGF, COX2, TNFa, IL-1b and MMP3 were determinated by Western Blot. Results In the OA rabbits, subchondral BMD decreased in relation to control, been partially reversed in the tibiae of TM-OA group. When subchondral trabecular bone structural parameters were analyzed by microCT, a significant decrease of bone volume/trabecular volume (BV/TV), trabecular number (Tb.N) and trabecular thickness (Tb.Th) was observed in the OA rabbits, while trabecular separation (Tb.S) increased compared to control animals. TM-OA group showed a significant improvement of these parameters compare to FM-OA group. FM-OA joints had higher Mankin score (cartilage damage) than control joints, and TM decreased Mankin score compare to FM-OA (p Conclusion These results suggest that mechanical stimulus induced by CM may retard the pathologic progression of OA. The beneficial effects of CM might be associated with an improvement in bone and cartilage damage and also inflammatory state. Disclosure of Interests None declared

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, osteophyte formation, subchondral bone sclerosis, and synovitis. Systemic factors such as obesity and the components of the metabolic syndrome seem to contribute to its progression. Breakdown of cartilage ensues from an altered balance between mechanical overload and its absorption by this tissue. There is in this context a status of persistent local inflammation by means of the chronic activation of innate immunity. A broad variety of danger-associated molecular patterns inside OA joint are able to activate pattern recognition receptors, mainly TLR (toll-like receptor) 2 and 4, which are overexpressed in the OA cartilage. Chronic activation of innate immune responses in chondrocytes results in a robust production of pro-inflammatory cytokines and chemokines, as well as of tissue-destructive enzymes, downstream of NF-κB and MAPK (mitogen activated protein kinase) dependent pathways. Besides, the toxic effects of an excess of glucose and/or fatty acids, which share the same pro-inflammatory intracellular signalling pathways, may add fuel to the fire. Not only high concentrations of glucose can render cells prone to inflammation, but also AGEs (advanced glycation end products) are integrated into the TLR signalling network through their own innate immune receptors. Considering these mechanisms, we argue for the control of both primary inflammation and proteolytic catabolism as a preventive strategy in OA, instead of focusing treatment on the enhancement of anabolic responses. Even though this approach would not return to normal already degraded cartilage, it nonetheless might avoid damage extension to the surrounding tissue.

Aging is a natural process characterized by the declining ability of the different organs and tissues to respond to stress, increasing homeostatic imbalance and risk of disease. Osteoarthritis (OA) is a multifactorial disease in which cartilage degradation is a central feature. Aging is the main risk factor for OA. In OA cartilage, a decrease in the number of chondrocytes and in their ability to regenerate the extracellular matrix and adequately respond to stress has been described. OA chondrocytes show a senescence secretory phenotype (SSP) consisting on the overproduction of cytokines (interleukins 1 and 6), growth factors (e.g., epidermal growth factor) and matrix metalloproteinases (MMP) (e.g., MMP-3, MMP-13). Reactive Oxygen Species (ROS) play a major role in the induction of the SSP. In chondrocytes, an increase in ROS production leads to hyper-peroxidation, protein carbonylation and DNA damage which alter chondrocyte function. ROS overproduction also induces changes in metabolic pathways such as PI3K-Akt and ERK. Autophagy is a key mechanism for maintaining cell homeostasis by adjusting cell metabolism to nutrient supply and removing damaged organelles. In cartilage, aging-related loss of autophagy leads to cell death and OA, while stimulation of autophagy exerts protective effects on cartilage deterioration. Aging also interferes with epigenetic mechanisms such as activity of histone acetylases that control the pattern of DNA methylation, and induces up- or down-regulation of microRNAs expression. A deeper knowledge of the mechanisms involved in chondrocyte aging could identify potential targets for the treatment of OA, a prevalent and therapeutic-orphan disease.

Objectives Despite the high prevalence of osteoarthritis (OA) in postmenopausal women, a relationship between circulating estrogen levels and the development of OA has not been found. Therefore, the purpose of this study was to evaluate the expression and activity of aromatase, a key enzyme in local production of estrogens, in human OA cultured articular chondrocytes, and to determine the physiological relevance of this enzyme in cartilage. Methods Human OA articular chondrocytes were isolated and cultured. Local production of estradiol was measured after incubation with 100ng/ml testosterone for 8 and 24 h. Furthermore, chondrocytes were culture for 2 h, 48 h, 7 days or 15 days, or in alginate beads for 10 days. Aromatase, type II and X collagen, aggrecan, alkaline phosphatase, and Runx2 expression were evaluated in cartilage, freshly isolated chondrocytes and cultured chondrocytes. Results Aromatase was expressed and active in cultured human chondrocytes. Human cartilage, freshly isolated chondrocytes, and chondrocytes cultured for 2 h expressed an insignificant amount of aromatase; however, expression arose after 48 h of culture and remained increased thereafter. Aromatase expression was not related to estrogen deprivation and was inversely correlated with differentiation. Re-differentiation did not reduce its expression. Conclusions Aromatase presents an almost undetectable expression in human cartilage but is induced in cultured chondrocytes. Therefore, human cartilage might act as a mere target for estrogens rather than a producer, and researchers using cell expansion in culture for latter therapies should consider these changes in estrogen metabolism which may not be reverted after re-differentiation.

Background Osteoarthritis (OA) is a complex joint disease characterised by a progressive lost of articular cartilage (AC), synovial inflammation and subchondral bone alterations. The latest theories of OA pathogenesis implicate the interplay between mechanical damage and chronic inflammation that has been associated to the activation of the innate immune system, intricately involved in the development of this low-grade inflammation. During the course of OA, Toll like receptor (TLR) activation has been related to the release of cytokines and inflammatory mediators, which further aggravate synovitis and AC damage.1 In this scenario, hyaline chondrocytes seem to acquire a hypertrophic-like phenotype associated to AC degradation. 6-shogaol (6S), an effective anti-inflammatory Ginger derivative, is able to inhibit TLR4-mediated innate immune responses.2 Objectives Our aim was to study the therapeutic benefit of 6-shogaol studying its anti-inflammatory effects in an OA mice model, and in the modulation of hypertrophic markers in chondrocyte cultures. Methods C57BL/6 male mice were randomly assigned to two groups: control (n=7) and OA (n=17). OA was induced by transection of the medial menisco-tibial ligament. Nine OA mice started receiving 6S (15 mg/kg/day; OA +6S) since surgery. After 8 weeks, animals were euthanized and joints were collected. Chondrogenic differentiation was induced in vitro in the pre-chondrogenic cell line ATDC5 in presence or absence of 5 × 10–6M 6S. Gene expression of hypertrophic markers, as well as mineralization and proteoglycan synthesis were determined. Results Both synovial inflammation and AC damage were more severe in OA animals (Control: 0.1±0.1; OA: 3.0±0; p Conclusions Our results showed that 6S significantly prevented cartilage degradation and synovial inflammation, in parallel to a reduction in the presence of hypertrophic markers in the cartilage of OA mice. In vitro, 6S inhibited the chondrogenic differentiation of ATDC5 cells. These results suggest that 6S could work as a good treatment in OA both inhibiting differentiation markers and reducing the severity of joint damage in an OA murine model. References [1] Gomez R, et al. Nat Rev Rheumatol2015. [2] Villalvilla A, et al. J Mol Nutr Food Res2013. Disclosure of Interest P. Gratal: None declared, A. Lamuedra: None declared, A. Mediero Grant/research support from: CP15/00053 PI16/00991, G. Herrero-Beaumont Grant/research support from: PI16/00065, R. Largo Grant/research support from: PI15/00340

Background Osteoarthritis (OA) is a degenerative joint disease characterised by the degradation and inflammation of cartilage and synovium with bone damage. Different approaches that decrease subchondral bone remodelling during OA have demonstrated to improve cartilage damage and synovial inflammation. Chiropractic is a therapeutic approach focused on the diagnosis, treatment and prevention of musculoskeletal disorders. Chiropractic manipulation (CM) is essentially manual, allowing the chiropractor to restore the normal range of motion and function of the joints, muscles, and ligaments. We have previously observed that CM is able to increase subchondral bone mineral density (BMD) in an experimental model of osteoporosis1. Objectives To evaluate if CM could prevent the subchondral BMD alterations induced by OA, in association to an improvement in synovial membrane inflammation and cartilage damage in an OA model in rabbits. Methods Ten male New Zealand rabbits were submited knee surgery to induce OA by transection of anterior cruciate ligament. CM was performed using the chiropractic adjusting instrument ActivatorV 3 times a week during 8 weeks as follows: Force 2 setting was applied onto the tibial tubercle of the rabbit right hind limb (CM-OA group), at an angle of 90°, whereas the corresponding left hind limb received a false manipulation (FM-OA group) consisting of ActivatorV firing in the air and touching the tibial tubercle. Three healthy animals were used as controls. Following sacrifice, tibiae and femora were removed for mCT and histological evaluation. Synovial inflammation was evaluated by Krenn’s score and the protein presence of VEGF, MMP3 and CollagenVI in the synovial membrane was evaluated by western blot. Results In the OA rabbits, subchondral BMD decreased in relation to control animals (OA 4729±193 vs Control 5181±209 mg/cc), been partially reversed in the tibiae of OA rabbits with CM (TM-OA 5055±216 vs FM-OA 4404±170 mg/cc). Subchondral trabecular bone structural parameters were analysed by microCT and a significant decrease of bone volume/trabecular volume (BV/TV), trabecular number (TbN) and trabecular thickness (TbTh) was observed in the OA rabbits, while trabecular separation (TbS) increased compared to control animals. TM-OA group showed a significant improvement of these parameters compare to FM-OA group. TM-OA had lower cartilage damage compare to FM-OA (TM-OA 4±0,67 AU vs FM-OA 8±1,25 AU). TM-OA synovial membranes presented a total Krenn score lower than FM-OA joints (TM-OA 3±0,35 vs FM-OA 4.5±0,38 AU). OA synovial membranes showed higher levels of CollagenVI respect to control ones; TM-OA synovial membranes presented less expression of CollagenVI than FM-OA group (TM-OA 1.4±0,13 vs FM-OA 2.2±0,3 AU), been this associated with a decrease of both MMP3 (TM-OA 1.2±0,1 vs FM-OA 1.7±0.2 AU) and VEGF (TM-OA 1.2±0.14 vs FM-OA 1.9±0.26 AU). Conclusions These results support the hypothesis that CM may ameliorate subchondral BMD alterations induced by OA, in association to an improvement on synoviopathy and cartilage degradation. Reference [1] Lopez-Herradon A, et al. Impact of Chiropractic Manipulation on Bone and Skeletal Muscle of Ovariectomized Rats.CalcifTissueInt2017;101(5):519–529. Disclosure of Interest F. Conesa: None declared, R. Fujikawa: None declared, A. Mediero Grant/research support from: CP15/00053 PI16/00991, P. Gratal: None declared, F. Mulero: None declared, G. Herrero-Beaumont Grant/research support from: PI16/00065, R. Largo Grant/research support from: PI15/00340, A. Ortega-de Mues: None declared

Background Metabolic syndrome (MetS) may be associated with knee osteoarthritis (OA), but the association between the individual components and OA are not well-understood. We aimed to study the effect of hypercholesterolemia on synovial inflammation in knee OA. Methods OA was surgically induced in rabbits fed with standard diet (OA group, n = 10) or in rabbits fed with high fat diet (OA-HFD, n = 10). Healthy rabbits receiving standard diet (Control, n = 10) or fed with HFD (HFD, n = 6) were also monitored. Twelve weeks after OA induction, synovial membranes were isolated and processed for studies. Results Animals fed HFD showed higher levels of total serum cholesterol, triglycerides and C-reactive protein than control rabbits. Twelve weeks after OA induction, synovial membrane inflammation and macrophage infiltration were increased in rabbits with OA, particularly in the OA-HFD group. Extensive decrease of synovial adipose tissue area, adipocyte size and perilipin-1A synthesis were observed in the OA-HFD group in comparison to the OA and control groups. The HFD further increased the proinflammatory mediators IL-1β, IL-6 and TNF in the OA synovium. However, the synovial gene expression of adipokines, such as leptin and adiponectin, were markedly decreased in the rabbits with OA, especially in the OA-HFD group, in correlation with adipose tissue loss. However, circulating leptin was upregulated in the HFD and OA-HFD groups. Conclusion Our results indicate that a HFD is an aggravating factor worsening synovial membrane inflammation during OA, guided by increased infiltration of macrophages and removal of the adipose tissue, together with a remarkable presence of proinflammatory factors. Synovial adipocytes and dyslipemia could probably play pivotal roles in OA joint deterioration in patients with MetS, supporting that the link between obesity and OA transcends mechanical loading. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1473-z) contains supplementary material, which is available to authorized users.

Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs).

Stromal cell-derived factor 1 (SDF-1) is a potent chemoattractant cytokine with various biological functions such as stem cell mobilization, inflammatory cell infiltration and angiogenesis. Therefore, it has also been implicated in several pathological processes, from ischemic conditions to cancer. Remarkably, SDF-1 and its receptors, CXCR4 and CXCR7, are also present in joint tissues, where they play a role in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA).This review summarizes the physiological and pathological role of SDF-1 signaling and its involvement in RA and OA. That includes synovial inflammation, bone erosion, cartilage degradation and increased bone turnover. Although this cytokine could play different roles in these rheumatic diseases, specific and differentiated therapeutic targets in each process can be identified. Current therapeutic strategies to block SDF-1 signaling in several diseases and their possible use in rheumatic diseases are also discussed.Emerging drugs that block CXCR4 or CXCR7 in different disorders may represent promising therapies for rheumatic disease via inhibition of key pathological events involved in the progression of RA and OA.

Background Osteoarthritis (OA) joints display relevant microstructure alterations associated to an increase in remodeling at subchondral bone, which supports its crucial role in OA pathogenesis. Despite this, the treatment of knee OA patients with antiresorptive drugs has given discordant results, suggesting the existence of a particular patient subset with good response to halting high subchondral remodeling. Objective To identify an OA phenotype that may obtain major benefit from therapy with bone-acting agents. Methods A systematic review of the literature was performed by searching the Medline and PubMed databases from 1990 to April 2013 using the following keywords: subchondral bone, articular cartilage, and osteoarthritis in various combinations with bone agents, bone mineral density, and scintigraphy. Results Early animal and human studies provided the rationale for the beneficial use of bone agents on OA cartilage damage. Several bone-acting agents have reduced low back pain and likely spondylosis progression. Recently, strontium ranelate has been reported to exert both structural and clinical benefits in knee OA patients with radiological progression. However, other antiresorptives have shown divergent results. Human studies suggest that these contradictory results may be due to the lack of well-defined OA phenotypes and an accurate methodology to recruit and follow up these patients. Conclusions A particular subset of postmenopausal patients with high remodeling and/or low subchondral bone density may benefit from the treatment with bone-acting agents hindering OA progression. This OA population could be identified with the simultaneous use of subchondral bone dual-energy X-ray absorptiometry and scintigraphy.

Summary Objective There is increasing evidence that the addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins plays an important role in cell signaling pathways. In chondrocytes, accumulation of O-GlcNAc-modified proteins induces hypertrophic differentiation. Osteoarthritis (OA) is characterized by cartilage degradation, and hypertrophic-like changes in hyaline chondrocytes. However, the mechanisms responsible for these changes have not been described. Our aim was to study whether O-GlcNAcylation and the enzymes responsible for this modification are dysregulated in the cartilage of patients with knee OA and whether interleukin-1 could induce these modifications in cultured human OA chondrocytes (HOC). Design Human cartilage was obtained from patients with knee OA and from age and sex-matched healthy donors. HOC were cultured and stimulated with the catabolic cytokine IL-1α. Global protein O-GlcNAcylation and the synthesis of the key enzymes responsible for this modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), were assessed by western blot. Results OA was associated with a 4-fold increase in the global O-GlcNAcylation in the cartilage. OA cartilage showed a re-distribution of the OGT and OGA isoforms, with a net increase in the presence of both enzymes, in comparison to healthy cartilage. In HOC, IL-1α stimulation rapidly increased O-GlcNAcylation and OGT and OGA synthesis. Conclusions Our results indicate that a proinflammatory milieu could favor the accumulation of O-GlcNAcylated proteins in OA cartilage, together with the dysregulation of the enzymes responsible for this modification. The increase in O-GlcNAcylation could be responsible, at least partially, for the re-expression of hypertrophic differentiation markers that have been observed in OA.

cope Ginger has long been used in traditional Asian medicine to treat osteoarthritis. Indeed, scientific research has reported that ginger derivatives (GDs) have the potential to control innate immune responses. Given the widespread use and demonstrated properties of GDs, we set out to study their anti-inflammatory and anticatabolic properties in chondrocytes. Methods and results 6-shogaol (6-S), the most active GD, was obtained from ginger. 6-S was not toxic as measured by MTT assay, and inhibited NO production and IL-6 and MCP-1 induced gene expression in LPSbut not in IL-1β-stimulated chondrocytes. 6-S also inhibited LPS-mediated ERK1/2 activation as well as NOS2 and MyD88 induced expression as determined by Western blot. Moreover, zymography revealed that 6-S inhibited matrix metalloproteinases (MMP) 2/9 induction in LPS-treated cells. Hydrated 6-S was modified to obtain a compound (SSi6) without 6-S potential anti-inflammatory properties. Both 6-S and SSi6 inhibited cathepsin-K activity. Conclusion 6-S blocked TLR4-mediated innate immune responses and MMP induction in chondrocytes. These results, together with GDs-mediated cathepsin-K inhibition, suggest the potential for GDs use against cartilage and bone degradation. Therefore, considering that clinical trials involving oral administration of ginger achieved relevant nontoxic GDs serum concentrations, we suggest that a ginger-supplemented diet might reduce OA symptoms.

Osteoarthritis is the most common chronic joint disorder especially during aging. Although with controversies, glucosamine, both in its forms of sulfate and hydrochloride, and chondroitin sulfate are commonly employed to treat osteoarthritis. Due to the modest improve in the symptoms observed in patients treated with these drugs alone, a formulation combining both agents has been considered. The discrepant results achieved for pain control or structural improvement in osteoarthritis patients has been attributed to the quality of chemical formulations or different bias in clinical studies. The current study has been designed to test the effects of two different combined formulations with adequate pharmaceutical grade of these drugs in osteoarthritic joints, and to explore the underlying mechanisms modulated by both formulations in different osteoarthritis target tissues. Knee osteoarthritis was surgically induced in experimental rabbits. Some animals received the combined therapy (CT)1, (chondroitin sulfate 1200mg/day + glucosamine sulfate 1500mg/day), or the CT2 ((chondroitin sulfate 1200mg/day + glucosamine hydrochloride 1500mg/day). Neither CT1 nor CT2 significantly modified the cartilage damage or the synovial inflammation observed in osteoarthritic animals. Treatments were also unable to modify the presence of pro-inflammatory mediators, and the synthesis of metalloproteinases in the cartilage or in the synovium of osteoarthritic animals. Combined therapies did not modify the decrease in the subchondral bone mineral density observed in osteoarthritic rabbits. Therapies of chondroitin sulfate plus glucosamine sulfate or chondroitin sulfate plus glucosamine hydrochloride failed to improve structural damage or to ameliorate the inflammatory profile of joint tissues during experimental osteoarthritis.

The lack of a complete understanding of the complex processes involved in the etiopathogenesis and subsequent appropriate phenotyping makes it difficult to find therapies that may be efficacious in most patients with osteoarthritis (OA). Consensus recommendations involve mainly non-pharmacological approaches. Analgesics and NSAIDs are considered second choice options due to their poor efficacy/safety ratios. To some extent, OA may be considered an orphan disease. Therefore, there is an urgent need to identify effective and safe new pharmacologic modalities for treating OA.This review is based on a Medline comprehensive literature search for published articles evaluating new formulations of current drugs and promising emerging therapies in OA. We discuss the current status of novel systemic agents in development including potent analgesic options, inhibitors of innate immunity, inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines and cartilage proteases as well as bone agents. Furthermore, we also revise the potential benefit of intraarticular (IA) therapy with hyaluronic acid (HA), pro-inflammatory mediator blockers, cartilage anabolic agents, mesenchymal stem cell and gene transfer.Despite the renewed interest in the search of new compounds for treatment of OA, results have been limited. Novel systemic and IA administered agents are in active development. IA drug administration is particularly an attractive approach because can diminish some of the severe side effects associated with systemic drugs. Indeed, one of the most promising fields for pharmacology innovation in OA is joint injected therapy, as suggested by preliminary data from recent studies using IA sprifermin (rhFGF-18), mesenchymal stem cells or TGF-B1 transduced allogenic chondrocytes. Last, the effort to develop new drugs must be accompanied by the interest for establishing well-defined phenotypes, and only then, a more tailored therapy should be practiced in OA.

Objective To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA). Methods A multicenter, randomized, double-blind, placebo-controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate-to-severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy. Results Intriguingly, in the modified intent-to-treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm [19% reduction] in patients receiving CS plus GS versus −20.5 ± 2.4 mm [33% reduction] in patients receiving placebo; peak between-group difference in global pain score at 6 months 8.7 mm [14.2%], P

Osteoarthritis (OA), the most common form of arthritis, is a debilitating and progressive disease that has become a major cause of disability and impaired quality of life in the elderly. OA is considered an organ disease that affects the whole joint, where the subchondral bone (SB) plays a crucial role. Regardless of whether SB alterations precede cartilage damage or appear during the evolution of the disease, SB is currently recognised as a key target in OA treatment. In fact, bone abnormalities, especially increased bone turnover, have been detected in the early evolution of some forms of OA. Systemic osteoporosis (OP) and OA share a paradoxical relationship in which both high and low bone mass conditions may result in induction and/or OA progression. Recent findings suggest that some drugs may be useful in treating both processes simultaneously, at least in a subgroup of patients with OA and OP. This review focuses on the role of SB in OA pathogenesis, describing relevant underlying mechanisms involved in the process and examining the potential activity as disease-modifying anti-osteoarthritic drugs (DMOADs) of certain SB-targeting agents currently under study.

The newly published findings from the Chondroitin Versus Celecoxib Versus Placebo Trial (CONCEPT) underscore the complexity of performing clinical trials in the field of knee osteoarthritis. But do the results of CONCEPT merit the consideration of chondroitin sulfate as a first-line therapy?

The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents that are generally effective only for acute symptom relief. Compounds are currently being searched for that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar shortterm symptomatic effect, but also control the progression of the disease in the long-term. Glucosamine sulfate is, so far, the only drug that has demonstrated a combined symptom-modifying and potential structure-modifying effect in knee osteoarthritis when used as the prescription crystalline glucosamine sulfate formulation at the dose of 1500 mg once daily. These effects may be explained by reversal of the proinflammatory and joint-degenerating effects of IL-1 through the inhibition of the cytokine intracellular signaling pathway. However, efficacy data obtained with this prescription glucosamine sulfate formulation may not be applicable to all glucosamine products available as generics or dietary supplements, owing to pharmacodynamic and pharmacokinetic reasons.

SummaryThe rheumatic diseases have been associated with accelerated atherosclerosis. Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by persistent synovial inflammation which leads to disability and structural changes in joints. Epidemiological studies have demonstrated an increased cardiovascular mortality in patients with RA. In these patients, atherosclerotic plaque occurs earlier, and it has a faster evolution than in general population. Atherosclerosis (AT) is also an inflammatory disease partly mediated by cytokines, many of them involved on chronic synovitis. Our group has developed a rabbit experimental model of AT aggravated by chronic arthritis to study inflammatory mechanisms involved on the progression of vascular lesions and their response to drugs. A preliminary study using this model suggests a beneficial effect of chondroitin sulphate (CS), a drug recommended for the treatment of osteoarthritis, in controlling AT lesions. Yet clinical trials should be conducted with this compound to address the same hypothesis in human studies.

Summary Objective To simultaneously study the effect of a selective cyclooxygenase-2 (COX-2) inhibitor and that of a classic non-steroidal anti-inflammatory drug (NSAID) on the expression of pro-inflammatory genes in the cartilage of patients with severe knee osteoarthritis (OA) and in cultured human OA chondrocytes. Methods A 3-month clinical trial was carried out on 30 patients with severe knee OA scheduled for knee replacement surgery. Patients were randomized into two groups: patients treated with celecoxib (CBX) and patients treated with aceclofenac (ACF). OA patients who did not want to be treated served as the control group. After surgery, cartilage was processed for molecular biology studies. We also employed cultured chondrocytes from different OA patients to examine NSAID effects on pro-inflammatory gene expression in cells stimulated with interleukin (IL)-1β. Results Both CBX and ACF inhibited COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and inducible nitric oxide synthase (iNOS) synthesis in the articular cartilage of OA patients. In cultured chondrocytes, both NSAID decreased COX-2 and mPGES-1 synthesis and prostaglandin E2 (PGE2) release induced by IL-1β, while no effect was observed on nitric oxide or iNOS synthesis. In OA patients, only CBX decreased tumor necrosis factor alpha and IL-1β expression in the cartilage, while both NSAID diminished IL-1β induced cytokine synthesis in cultured OA chondrocytes. Conclusions Both NSAID diminished PGE2 release and induced a decrease in COX-2 and mPGES-1 synthesis in the cartilage from OA patients and in OA chondrocytes. These data suggest that prolonged therapy with PGE2 blocking agents decreases PGE2 production not only by direct inhibition of COX-2 activity, but also by down-regulating COX-2 and mPGES-1 synthesis in the cartilage. However, CBX and ACF seem to have a different anti-inflammatory profile in controlling pro-inflammatory gene expression in the cartilage.

Introduction Subchondral bone mineral density (sBMD) contributes to the initiation and progression of knee osteoarthritis (OA). Reliable methods to assess sBMD status may predict the response of specific OA phenotypes to targeted therapies. While dual-energy X-ray absorptiometry (DXA) of the knee can determine sBMD, no consensus exists regarding its methodology. Objective Construct a semi-standardized protocol for knee DXA to measure sBMD in patients with OA of the knee by evaluating the varying methodologies present in existing literature. Methods We performed a systematic review of original papers published in PubMed and Web of Science from their inception to July 2014 using the following search terms: subchondral bone, osteoarthritis, and bone mineral density. Results DXA of the knee can be performed with similar reproducibility values to those proposed by the International Society for Clinical Densitometry for the hip and spine. We identified acquisition view, hip rotation, knee positioning and stabilization, ROI location and definition, and the type of analysis software as important sources of variation. A proposed knee DXA protocol was constructed taking into consideration the results of the review. Conclusions DXA of the knee can be reliably performed in patients with knee OA. Nevertheless, we found substantial methodological variation across previous studies. Methodological standardization may provide a foundation from which to establish DXA of the knee as a valid tool for identification of SB changes and as an outcome measure in clinical trials of disease modifying osteoarthritic drugs.

Objective: To compare the effect of celecoxib with that of a classic non-steroidal anti-inflammatory drug (NSAID) on synovial inflammation and on the synovial expression of proinflammatory genes in patients with knee osteoarthritis (OA). Methods: 30 patients with severe knee OA scheduled for total knee replacement surgery were included in a 3 month clinical trial. They were randomised to two groups: patients treated with celecoxib (CBX) (200 mg/24 h) and patients treated with aceclofenac (ACF) (100 mg/12 h). Those patients with OA who did not want to be treated with NSAIDs served as a control group. During knee surgery, synovial fluid (SF) and synovial membrane (SM) were collected. A SM specimen was fixed and embedded in paraffin and another part was frozen for molecular biology studies. Results: At the end of study both CBX and ACF treated patients showed a significant improvement in pain and knee function compared with controls. Both drugs significantly reduced prostaglandin E 2 (PGE 2 ) SF concentration and down regulated COX-2 mRNA and protein expression at the SM. However, synovial macrophage infiltration (CD68 antigen staining) and expression of proinflammatory mediators, such as interleukin 1β and tumour necrosis factor α, were decreased only by CBX treatment. Conclusion: Both drugs improved joint pain and function, inhibited SF PGE 2 concentration, and induced a decrease in synovial COX-2 expression and synthesis not related to the tissue inflammatory status. These data suggest that PGE 2 blocking agents may decrease PGE 2 production not only by direct COX-2 inhibition but also by down regulating COX-2 expression and synthesis. However, CBX and ACF appear to have different anti-inflammatory profiles in controlling OA synovial macrophage infiltration and proinflammatory expression.

Objective Glucosamine sulfate (GS) is a commonly used drug for the treatment of osteoarthritis. The mechanism of the action of this drug does, however, remain to be elucidated. In human osteoarthritic chondrocytes (HOC) stimulated with a proinflammatory cytokine, we studied whether GS could modify the NFkappaB activity and the expression of COX-2, a NFkappaB-dependent gene. Methods Using HOC in culture stimulated with interleukin-1 beta (IL-1beta), the effects of GS on NFkappaB activation, nuclear translocation of NFkappaB/Rel family members, COX-1 and COX-2 expressions and syntheses and prostaglandin E2 (PGE2) concentration were studied. Results GS significantly inhibited NFkappaB activity in a dose-dependent manner, as well as the nuclear translocation of p50 and p65 proteins. Furthermore, GS-preincubated IL-1beta-stimulated HOC showed an increase in IkappaBalpha in the cell cytoplasm in comparison with HOC incubated with IL-1beta alone. GS also inhibited the gene expression and the protein synthesis of COX-2 induced by IL-1beta, while no effect on COX-1 synthesis was seen. GS also inhibited the release of PGE2 to conditioned media of HOC stimulated with IL-1beta. Conclusions GS inhibits the synthesis of proinflammatory mediators in HOC stimulated with IL-1beta through a NFkappaB-dependent mechanism. Our study further supports the role of GS as a symptom- and structure-modifying drug in the treatment of OA.

The dramatic rise in the prevalence rate of osteoarthritis (OA) after the menopause and the presence of estrogen receptors in joint tissues suggest that estrogen may help protect against the development of OA. Trials of estrogen therapy have produced inconclusive results, however, partly because of flaws in study design and partly because of the complexity of the mechanisms underlying estrogen's effects on joint tissues. Initial studies of the use of selective estrogen receptor modulators (SERMs) have reported beneficial effects in OA. These agents may exert both a direct effect upon joint cartilage and indirect effects on subchondral bone, synovium, muscle, tendons and ligaments. SERMs may be particularly beneficial for postmenopausal patients with osteoporotic OA, a phenotype defined by decreased bone density, associated with high remodeling in subchondral bone. More research is needed, though, before SERMs can become a therapeutic option for OA.

Osteoarthritis (OA) emerges of the inharmonious functioning of joint tissues, particularly subchondral bone (SB) and articular cartilage that are two mechanically and biologically intertwined tissues [1]. Thus, biomechanical, biochemical and/or genetic alterations affecting any joint tissue may cause anomalous intra-articular stresses and subsequent tissue damage associated to a failure of repair [2]. Specific anatomical regions have been described in the bone underlying joint cartilage, including the subchondral cortical plate, subchondral trabecular bone and sub-articular bone [3]. Each region likely contributes differently to cartilage pathology. However, a lack of clear boundaries between these tissues by current imaging techniques generates some confusion in their study and thorough research will help to improve our understanding of SB properties. In addition, bone at the joint margins is markedly active since is the site of osteophyte development in OA. The close relationship between SB and joint cartilage evokes an unanswered question with valuable therapeutic implications [4]. In this context, the relationship among SB microstructure and remodeling, and cartilage destruction becomes important. Yet, it remains controversial whether SB alterations precede the cartilage damage or they further appear during the evolution of the disease. In fact, SB remodeling abnormalities, especially increased bone turnover, have been detected early in the evolution of some forms of OA in animal models [5,6] and humans [7,8]. On the other hand, OA and systemic osteoporosis (OP) share a paradoxical relationship, being probable that high as well as low bone mass conditions result in induction and/or OA progression [4]. Interestingly, improving SB integrity showed to reduce the progression of cartilage damage in an animal model of OA preceded by OP [9]. Therefore, both bone mass phenotypes may be considered risk factors for OA initiation. The presence of other risk factors such as skeletal shape abnormalities, joint overload or obesity may have a synergistic effect for OA initiation. In addition, inflammatory mediators released by the articular cartilage may lead to SB loss by increasing bone remodeling in OA. Accordingly, OA treatment goals must consider the improvement of SB integrity. This therapeutic approach should be individualized depending on the patient BMD status and OA phenotype, and subsequently the use of drugs should also be individualized for each patient [10]. Recent findings suggest that the same drugs could be useful for treating simultaneously both processes, at least in a subgroup of patients with OA and concomitant OP.

SummaryPurposeSynoviopathy contributes to cartilage degradation in osteoarthritis (OA). Intermittent parathyroid hormone (PTH) [1-34] administration inhibits terminal differentiation of human chondrocytes and prevents cartilage damage. We aimed to determine whether PTH [1-34] could modify synovial changes in experimental OA preceded by osteoporosis (OP).MethodsTwenty osteoporosis (OP) rabbits underwent knee surgery to induce OA. They were administered either saline vehicle or PTH for 10 weeks. Ten healthy rabbits were used as controls. Following sacrifice, synovial changes were assessed by Krenn synovitis score, immunohistochemistry for macrophages (RAM-11), B and T lymphocytes, type I collagen, parathyroid hormone 1 receptor (PTH1R), and anti-proliferating cell nuclear antigen (PCNA). Synovial mRNA levels of Col1A1, IL-1β, cyclooxygenase 2 (COX-2), matrix-degrading metalloproteinases (MMP-9, MMP-13), and monocyte chemotactic protein-1 (MCP-1), as well as protein expression of PTH1R were also determined. Cartilage damage was analyzed by Mankin score.ResultsOPOA + vehicle rabbits showed an increase in synovitis score vs controls (P = 0.003), mainly due to synovial hyperplasia and fibrosis, while PTH reduced these changes (P = 0.017). Mankin and Krenn scores were well correlated in all groups (r = 0.629, P = 0.012). Immunostaining for RAM-11 and B lymphocytes was increased (P ≤ 0.05), whereas PTH1R protein levels tended to be higher in OPOA + vehicle animals vs controls. PTH did not modify RAM-11 staining or PTH1R levels; however, it restored PTH1R localization to the vicinity of synovial vessels. PTH also decreased type I collagen, MCP-1, and MMP-13 expression (P