Impact of barrier tissue inflammation and physical activity on joint homeostasis in mice.

OBJECTIVES: To investigate whether physical activity interferes with joint homeostasis in the presence of distant inflammation originating at barrier tissues such as skin or gut. METHODS: Eight-week-old male C57/Bl6 mice were treated with imiquimod cream on a shaved area of the back skin or with dextran sodium sulphate dissolved in the drinking water to induce psoriasis-like skin or inflammatory bowel disease-like gut inflammation. Afterwards, one group of mice was subjected to a 4-week forced running routine (n = 10 per group). Severity of cutaneous or intestinal inflammation was assessed clinically, by histology and by quantitative PCR. Knees and paws were analysed by micro-CT, histology, immunohistochemistry, second-harmonic generation microscopy and quantitative PCR. RESULTS: Local induction of inflammation triggered a systemic response with splenomegaly, loss of bone mass and bone marrow changes. Psoriasis- but not inflammatory bowel disease-like inflammation led to synovial lining layer hyperplasia, an increase in infiltrating CD45+ synovial cells, and suppressed entheseal extracellular matrix gene expression levels. Mechanical loading decreased the amount of F4/80+ synovial macrophages in untreated mice only and led to morphological alterations in the collagen fibres of the enthesis. CONCLUSION: Systemic inflammation and mechanical loading act independently of each other. The former, originating from distant sites, can trigger mild synovial inflammation in mice, a propensity that may also impact the development of arthritis in patients; the latter has no impact on the severity of systemic inflammation, but independently affects joint homeostasis.

Behavior of metastatic breast cancer according to subtype.

PURPOSE: To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS). METHODS: Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000-2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan-Meier method and logistic/Cox regression. RESULTS: After median follow-up time of 103.6 months (IQR 73.4-139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2-) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER-) without trastuzumab 30.0%, HER2Positive(ER-) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months). CONCLUSIONS: Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

Spondyloarthritis on the Move: Biomechanical Benefits or Harm.

PURPOSE OF REVIEW: Physical activity is beneficial in several diseases including spondyloarthritis despite mechanical stress being suggested as a trigger of disease onset or activity. Moreover, there is no clear answer as to where physiological loading of the joints ends and pathological overloading begins. The aim of this review is to provide an overview of what is known about exercise and biomechanical loading in spondyloarthritis. RECENT FINDINGS: Recent studies focused on the impact of mechanical loading in healthy individuals and spondyloarthritis patients, demonstrating an overlap between the groups and pointing out possible beneficial and detrimental activities. The discovery that several animal models of inflammatory arthritis are dependent on mechanical stress helps unraveling the involved molecular pathways. There is a knowledge gap between the beneficial effect of exercise reported in clinical trials and the harm seen in observational studies and animal models. Imaging studies provide a first step in joining these two opposites by highlighting a wide-ranging spectrum between healthy and diseased joints. Future research is warranted on specific interventions in well-defined patient populations and in animal models in order to understand the pathogenesis. Targeted exercise therapy and prevention should be considered specific goals.

Bone Disease in Axial Spondyloarthritis.

Axial spondyloarthritis is a chronic inflammatory skeletal disorder with an important burden of disease, affecting the spine and sacroiliac joints and typically presenting in young adults. Ankylosing spondylitis, diagnosed by the presence of structural changes to the skeleton, is the prototype of this disease group. Bone disease in axial spondyloarthritis is a complex phenomenon with the coexistence of bone loss and new bone formation, both contributing to the morbidity of the disease, in addition to pain caused by inflammation. The skeletal structural changes respectively lead to increased fracture risk and to permanent disability caused by ankylosis of the sacroiliac joints and the spine. The mechanism of this new bone formation leading to ankylosis is insufficiently known. The process appears to originate from entheses, specialized structures that provide a transition zone in which tendon and ligaments insert into the underlying bone. Growth factor signaling pathways such as bone morphogenetic proteins, Wnts, and Hedgehogs have been identified as molecular drivers of new bone formation, but the relationship between inflammation and activation of these pathways remains debated. Long-standing control of inflammation appears necessary to avoid ankylosis. Recent evidence and concepts suggest an important role for biomechanical factors in both the onset and progression of the disease. With regard to new bone formation, these processes can be understood as ectopic repair responses secondary to inflammation-induced bone loss and instability. In this review, we discuss the clinical implications of the skeletal changes as well as the underlying molecular mechanisms, the relation between inflammation and new bone formation, and the potential role of biomechanical stress.

Microtrauma: no longer to be ignored in spondyloarthritis?

PURPOSE OF REVIEW: Novel clinical and animal model data support that biomechanical factors play a role in the onset and progression of spondyloarthritis. Bringing together these insights with the progress made in our understanding of the immunopathogenesis and genetic susceptibility of spondyloarthritis may provide new opportunities for better management. RECENT FINDINGS: Tail suspension prevents arthritis in a tumor necrosis factor overexpression model. A similar approach also reduces new bone formation after acute arthritis in mice. Physical labor is associated with disease severity, including structural disease progression. Sentinel immune cells in the enthesis provide a link between local damage and the development of inflammation. Loss of stability likely triggers tissue remodeling, including the formation of syndesmophytes. Improving muscle strength and control while avoiding excessive strain or overuse should be considered in the approach toward patients. New regulators of tissue turnover and remodeling are emerging including microRNAs. SUMMARY: Local damage may provide a trigger for spondyloarthritis. For structural disease progression loss of stability may be an important factor. Control of inflammation will prevent stability issues and improve the long-term prognosis of disease. Physical therapy will continue to provide benefit for patients in the short and in long-term management of disease.