Osteoarthritis: at the crossroads of metabolism and inflammation

This thesis aimed to investigate how metabolic overload contributes to the pathophysiology of knee OA. We explored the role of these independent yet intertwined processes using state-of-the-art lipidomic and cellular approaches in mouse models of diet-induced OA. Chapter 2 presents an overview of twelve preclinical studies in which mice received various high-caloric diets at variable duration. From this comprehensive overview we deduced that diet-induced metabolic overload per se does not necessarily lead to aggravated articular cartilage degradation. The studies that demonstrated aggravated cartilage degradation were performed in mouse strains transgenic for human proteins involved either in inflammation or lipoprotein metabolism. We suggest that an additional trigger, other than high-caloric feeding alone, is necessary to evoke metabolic OA. To evaluate whether nutritional fat could indeed aggravate OA progression, low- and high-fat feeding was combined with a mild mechanical stressor (Chapter 3). OA onset was induced by microsurgical destabilization of the medial meniscus (DMM) in C57BL/6J mice. High-fat diet (HFD) feeding increased OA severity in this model and our findings point to a role for both lipid dysregulation and monocyte activation in disease pathogenesis. Based on these results, we suggest that these systemic factors might contribute to a diet-induced proinflammatory environment that enables aggravation of cartilage degeneration. To unravel the effects of a dysregulated lipid metabolism on the inflammatory state, we studied the development of metabolic inflammation both locally and systemically. In Chapter 4, we focussed on the inflammatory status of the infrapatellar fat pad (IFP) during OA progression. The most pronounced inflammation and a trend towards increased fibrosis was found in IFP of mice that received a HFD on top of a microsurgical trigger (DMM). These data suggest that HFD provides a priming effect on the IFP. Next, we addressed innate immune system involvement in the development of diet-induced OA. We provided male mice from a human C-reactive protein (hCRP) knock-in strain with an HFD for 38 weeks (Chapter 5). We demonstrated that hCRP-transgenic mice developed more severe OA compared with their wild-type controls under the same HFD regimen. This finding implicates CRP as an independent trigger to aggravate HFD-induced OA development. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. To expand on the outcomes of Chapters 3 and 5, in Chapter 6 we assessed the contribution of elevated plasma cholesterol levels to the severity of diet-induced OA. Cholesterol is involved in lipid metabolism as well as inflammation and is described to aggravate OA progression. We observed insignificant effects of therapeutic cholesterol-lowering on OA features and suggest that cholesterol-lowering treatments alone are probably not effective in preventing progression of pre-existent OA. Possibly, absence of inflammation in this model might explain the reduced effectiveness of cholesterol lowering, which bears implications for the clinical setting. In Chapter 7, the general discussion, we discuss the implications of findings described in this thesis and propose to view the metabolic OA subtype as a whole-body disease instead of a whole-joint disease

Poster OARSI 2016: Aggravated osteoarthritis development on a high fat diet in mice transgenic for human C-reactive protein

Metabolic overload is linked to OA development. The low-grade systemic inflammation associated with metabolic overload is a possible mechanism through which OA pathogenesis is mediated. Using a mouse strain transgenic for the human inflammation marker C-reactive protein (hCRP), we questioned whether inflammation plays a role in disease development in a murine metabolic OA model

Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet

OBJECTIVE: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA. DESIGN: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n=30) and wild-type littermates (n=15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets. RESULTS: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups. CONCLUSIONS: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development

Low-strength T-cell activation promotes Th17 responses

We show that the strength of T-cell stimulation determines the capability of human CD4(+) T cells to become interleukin-17 (IL-17) producers. CD4(+) T cells received either high- (THi) or low (TLo)–strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti-CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor β–latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca(2+) ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca(2+) signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses

Specialized pediatric palliative care services in pediatric hematopoietic stem cell transplant centers

Hematopoietic stem cell transplantation (HSCT) is widely used in pediatric patients as a successful curative therapy for life-threatening conditions. The treatment is intensive, with risks of serious complications and lethal outcomes. This study aimed to provide insight into current data on the place and cause of death of transplanted children, the available specialized pediatric palliative care services (SPPCS), and what services HSCT professionals feel the SPPCS team should provide. First, a retrospective database analysis on the place and cause of death of transplanted pediatric HSCT patients was performed. Second, a survey was performed addressing the availability of and views on SPPCS among HSCT professionals. Database analysis included 233 patients of whom the majority died in-hospital: 38% in the pediatric intensive care unit, 20% in HSCT units, 17% in other hospitals, and 14% at home or in a hospice (11% unknown). For the survey, 98 HSCT professionals from 54 centers participated. Nearly all professionals indicated that HSCT patients should have access to SPPCS, especially for pain management, but less than half routinely referred to this service at an early stage. We, therefore, advise HSCT teams to integrate advance care planning for pediatric HSCT patients actively, ideally from diagnosis, to ensure timely SPPCS involvement and maximize end-of-life preparation

Outcome of allogeneic haematopoietic stem cell transplantation in myeloproliferative neoplasm, unclassifiable: a retrospective study by the Chronic Malignancies Working Party of the EBMT

Myeloproliferative Neoplasm (MPN), unclassifiable (MPN-U) is a heterogeneous disease with regards to both clinical phenotype and disease course. Patients may initially be asymptomatic or present with leucocytosis or thrombocytosis, anaemia, progressive splenomegaly, constitutional symptom, thromboses or accelerated/blastic phase disease. Treatment strategies are variable and there are no widely accepted consensus management guidelines for MNU-U. Allogeneic Haematopoietic Cell Transplantation (allo-HCT) remains the only curative strategy yet outcomes, to date, are not well defined. We hereby report on the largest retrospective study of patients with MPN-U undergoing allo-HCT, highlighting the potentially curative role and providing clinicians with robust engraftment, GvHD and outcome data to facilitate patient discussion