Norepinephrine modulates IL-1β-induced catabolic response of human chondrocytes

Background The influence of the sympathetic nervous system (SNS) on metabolism of bone and cartilage expressing β-adrenergic receptors (AR) was suggested. Here, we investigated whether the SNS functions as a modulator of cartilage metabolism induced by interleukin-1beta (IL-1β). Methods Human articular chondrocytes and articular cartilage were collected from patients with osteoarthritis (OA). Chondrocyte monolayer and cartilage explant culture were stimulated with IL-1β. The activity of β-ARs was modulated by an agonist, norepinephrine (NE), and antagonists, including propranolol, atenolol, nebivolol, and nadolol. Results The levels of β1-, β2-, and β3-AR in OA cartilage and IL-1β-treated chondrocytes were lower than normal cartilage and untreated cells. Treatment of chondrocytes with IL-1β and β-blockers, including propranolol, atenolol, nebivolol, and nadolol, for 6 h significantly upregulated IL-1β-induced expression of MMP-1, -3, and − 13, compared to chondrocytes treated with IL-1β alone, indicating that antagonism of β-AR confers catabolic signals. On the other hand, NE antagonized IL-1β-induced catabolic response. In addition, NE significantly inhibited IL-1β-induced release of glycosaminoglycan (GAG) from cartilage explant culture. In addition, β-AR activity significantly affected IL-1β-stimulated phosphorylation of JNK and ERK. These results indicate that β-AR signal is associated with cartilage metabolism. Conclusions Our findings showed that β-ARs is a regulator of cartilage catabolism induced with IL-1β.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial

Background Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. Methods Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. Results Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). Conclusion The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. Trial registration details Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015.

Biomechanical-Based Protocol for in vitro Study of Cartilage Response to Cyclic Loading: A Proof-of-Concept in Knee Osteoarthritis

Osteoarthritis (OA) is an evolving disease and a major cause of pain and impaired mobility. A deeper understanding of cartilage metabolism in response to loading is critical to achieve greater insight into OA mechanisms. While physiological joint loading helps maintain cartilage integrity, reduced or excessive loading have catabolic effects. The main scope of this study is to present an original methodology potentially capable to elucidate the effect of cyclic joint loading on cartilage metabolism, to identify mechanisms involved in preventing or slowing down OA progression, and to provide preliminary data on its application. In the proposed protocol, the combination of biomechanical data and medical imaging are integrated with molecular information about chondrocyte mechanotransduction and tissue homeostasis. The protocol appears to be flexible and suitable to analyze human OA knee cartilage explants, with different degrees of degeneration, undergoing ex vivo realistic cyclic joint loading estimated via gait analysis in patients simulating mild activities of daily living. The modulation of molecules involved in cartilage homeostasis, mechanotransduction, inflammation, pain and wound healing can be analyzed in chondrocytes and culture supernatants. A thorough analysis performed with the proposed methodology, combining in vivo functional biomechanical evaluations with ex vivo molecular assessments is expected to provide new insights on the beneficial effects of physiological loading and contribute to the design and optimization of non-pharmacological treatments limiting OA progression.

Innate immunity, bone and cartilage metabolism in children with developmental dislocation of the hip – pilot study

Objective Search for the relationship between innate immunity and bone and cartilage metabolism in patients with developmental dislocation of the hip (DDH). Material and methods The study included 27 patients with DDH who underwent reduction of the hip at pediatric orthopaedic department of the Federal State Budgetary Educational Institution of Higher Education «Privolzhsky Research Medical University» of the Ministry of Health of the Russian Federation. The patients aged 15.0 ± 1.7 months. The study enrolled the babies diagnosed with grades III, IV, V unilateral or bilateral DDH as classified by M.V. Volkov, 1978. Patients with hip dysplasia (grade I DDH) or congenital hip subluxation (grade II DDH) were excluded from the study. The control group consisted of 15 patients without musculoskeletal pathology. The mean patients' age was 24.0 ± 1.8 months. Peripheral blood monocytes, toll-like receptor (TLR2, TLR4, TLR5) expression, serum concentrations of fibroblast growth factors (FGF), vascular endothelial growth factor (VEGF), serum magnesium, type I, II collagen and aggrecan were measured in patients of major and control groups. Results DDH patients showed statistically significant differences in all the parameters measured except for the type 2 collagen with decrease in peripheral blood monocyte and increase in TLR2 and TLR5 expression, slight increase in the serum magnesium with decreased concentration of aggrecan and increased FGF level. There was a two-fold decrease in VEGF level and a two-fold increase in type I collagen concentration. There were moderate significant correlations for monocyte matches TLR2 and TLR2 – TLR5 in major group. Three main factors detected with factor analysis included (1) monocytes, TLR2 and TLR5 as most meaningful, (2) FGF and type 2 collagen and (3) aggrecan. Conclusion The findings suggested that specific factors of innate immunity can be involved in the pathogenesis of DDH. Toll receptors regulate many metabolic pathways and connective tissue metabolism, More studies are needed to further explore this topic.

Norepinephrine Modulates IL-1β-induced Catabolic Response of Human Chondrocytes

BackgroundThe influence of the sympathetic nervous system (SNS) on metabolism of bone and cartilage expressing β-adrenergic receptors (AR) was suggested. Here, we investigated the relation between SNS and interleukin-1beta (IL-1β)-induced cartilage metabolism.MethodsHuman articular chondrocytes and articular cartilage were collected from patients with osteoarthritis (OA). Chondrocyte monolayer and cartilage explant culture were stimulated with IL-1β. The activity of β-ARs was modulated by an agonist, norepinephrine (NE), and antagonists, including propranolol, atenolol, nebivolol, and nadolol.ResultsThe levels of β1-, β2-, and β3-AR in OA cartilage and IL-1β-treated chondrocytes were lower than normal cartilage and untreated cells. Treatment of chondrocytes with IL-1β and β-blockers, including propranolol, atenolol, nebivolol, and nadolol, for 6 h significantly upregulated IL-1β-induced expression of MMP-1, -3, and -13, compared to chondrocytes treated with IL-1β alone, indicating that antagonism of β-AR confers catabolic signals. On the other hand, NE antagonized IL-1β-induced catabolic response. In addition, NE significantly inhibited IL-1β-induced release of glycosaminoglycan (GAG) from cartilage explant culture. In addition, β-AR activity significantly affected IL-1β-stimulated phosphorylation of JNK and ERK. These results indicate that β-AR signal is associated with cartilage metabolism.ConclusionsOur findings showed that β-ARs is a regulator of cartilage catabolism induced with IL-1β.

Shengu'an exerts anti-osteoporotic effect in rats via TGFβ1-Smad2/3 signal pathway, and enhancement of bone and cartilage metabolism

Purpose: To study the anti-osteoporotic effect of Shengu'an in rats, and elucidate the mechanism of action involved.Methods: Forty healthy female SPF mice were randomly divided into control group, saline-treated group, TGFβRⅡ receptor inhibitor group, and shengu'an group. The expressions of type Ⅱ collagen (Co1-II) and platelet endothelial cell adhesion factor (CD-31) were determined. The expressions of transforming growth factor β1 (TGF-β1), p-smad2/3, matrix metalloproteinase-9 (MMP-9) and osteoblast specific transcription factor (osterix) were assayed by western blotting.Results: The expression of Co1-II in the vertebral body was significantly lower in model mice than in control mice, but was significantly higher in shengu'an mice when compared with model mice (p < 0.05). In shengu'an mice, CoI-I was markedly upregulated, relative to model mice, and the expressions of CD31 in TGFβRⅡreceptor inhibitor group and shengu'an group were lower than in model group (p < 0.05). There were significantly lower expressions of TGF-β1 and p-smad2/3 in the vertebral body of shengu'an group than in model mice, but osterix was upregulated relative to model mice (p < 0.05).Conclusion: Shengu'an exerts anti-osteoporotic effect by downregulating TGFβ/smad signal pathway. There is thus a potential for its clinical application in the management of osteoporosis. Keywords: Shengu'an, TGFβ1-Smad2/3 signal, Bone cartilage metabolism, Osteoporosis