The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Serum levels of Cartilage Oligomeric Matrix Protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis

BACKGROUND: COMP (Cartilage oligomeric matrix protein) is a matrix protein, which is currently studied as a potential serum marker for cartilage processes in osteoarthritis (OA). The influence of physical exercise on serum COMP is not fully elucidated. The objective of the present study was to monitor serum levels of COMP during a randomised controlled trial of physical exercise vs. standardised rest in individuals with symptomatic and radiographic knee OA. METHODS: Blood samples were collected from 58 individuals at predefined time points before and after exercise or rest, one training group and one control group. The physical exercise consisted of a one-hour supervised session twice a week and daily home exercises. In a second supplementary study 7 individuals were subjected to the same exercise program and sampling of blood was performed at fixed intervals before, immediately after, 30 and 60 minutes after the exercise session and then with 60 minutes interval for another five hours after exercise to monitor the short-term changes of serum COMP. COMP was quantified with a sandwich-ELISA (AnaMar Medical, Lund, Sweden). RESULTS: Before exercise or rest no significant differences in COMP levels were seen between the groups. After 60 minutes exercise serum COMP levels increased (p < 0.001). After 60 minutes of rest the serum levels decreased (p = 0.003). Median serum COMP values in samples obtained prior to exercise or rest at baseline and after 24 weeks did not change between start and end of the study. In the second study serum COMP was increased immediately after exercise (p = 0.018) and had decreased to baseline levels after 30 minutes. CONCLUSION: Serum COMP levels increased during exercise in individuals with knee OA, whereas levels decreased during rest. The increased serum COMP levels were normalized 30 minutes after exercise session, therefore we suggest that samples of blood for analysis of serum COMP should be drawn after at least 30 minutes rest in a seated position. No increase was seen after a six-week exercise program indicating that any effect of individualized supervised exercise on cartilage turnover is transient

Proteoglycans and glycosaminoglycan fine structure in the mouse tail tendon fascicle

The isolated mouse tail tendon fascicle, a functional and homogenous volume of tendon extracellular matrix, was utilized as an experimental system to examine the structure–function relationships in tendon. Our previous work using this model system demonstrated relationships between mean collagen fibril diameter and fascicle mechanical properties in isolated tail tendon fascicles from three different groups of mice (3-week and 8-week control and 8-week Mov13 transgenic) K.A. Derwin, L.J. Soslowsky, J. Biomech. Eng. 121 (1999) 598–604. These groups of mice were chosen to obtain tendon tissues with varying collagen fibril structure and/or biochemistry, such that relationships with material properties could be investigated. To further investigate the molecular details of matrix composition and organization underlying tendon function, we report now on the preparation, characterization, and quantitation of fascicle PGs (proteoglycans) from these three groups. The chondroitin sulfate/dermatan sulfate (CS/DS)-substituted PGs, biglycan and decorin, which are the abundant proteoglycans of whole tendons, were also shown to be the predominant PGs in isolated fascicles. Furthermore, similar to the postnatal maturation changes in matrix composition previously reported for whole tendons, isolated fascicles from 8-week mice had lower CS/DS PG contents (both decorin and biglycan) and a higher collagen content than 3-week mice. In addition, CS/DS chains substituted on PGs from 8-week fascicles were shorter (based on a number average) and richer in disulfated disaccharide residues than chains from 3-week mice. Fascicles from 8-week Mov13 transgenic mice were found to contain similar amounts of total collagen and total CS/DS PG as age-matched controls, and CS/DS chain lengths and sulfation also appeared normal. However, both decorin and biglycan in Mov13 tissue migrated slightly faster on sodium dodecyl sulfate polyacrylamide gel electorphoresis (SDS-PAGE) than the corresponding species from 8-week control, and biglycan from the 8-week Mov13 fascicles appeared to migrate as a more polydisperse band, suggesting the presence of a unique PG population in the transgenic tissue. These observations, together with our biomechanical data [Derwin and Soslowsky, 1999] suggest that compensatory pathways of extracellular matrix assembly and maturation may exist, and that tissue mechanical properties may not be simply determined by the contents of individual matrix components or collagen fibril size. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34919/1/1100190216_ftp.pd

From Data Disclosure to Privacy Nudges: A Privacy-aware and User-centric Personal Data Management Framework

Although there are privacy-enhancing tools designed to protect users' online privacy, it is surprising to see a lack of user-centric solutions allowing privacy control based on the joint assessment of privacy risks and benefits, due to data disclosure to \emph{multiple} platforms. In this paper, we propose a conceptual framework to fill the gap: aiming at the user-centric privacy protection, we show the framework can not only assess privacy risks in using online services but also the added values earned from data disclosure. Through following a human-in-the-loop approach, it is expected the framework provides a personalized solution via preference learning, continuous privacy assessment, behavior monitoring and nudging. Finally, we describe a case study towards "leisure travelers" and several future areas to be studied in the ongoing project

Premature Osteoblast Clustering by Enamel Matrix Proteins Induces Osteoblast Differentiation through Up-Regulation of Connexin 43 and N-Cadherin

In recent years, enamel matrix derivative (EMD) has garnered much interest in the dental field for its apparent bioactivity that stimulates regeneration of periodontal tissues including periodontal ligament, cementum and alveolar bone. Despite its widespread use, the underlying cellular mechanisms remain unclear and an understanding of its biological interactions could identify new strategies for tissue engineering. Previous in vitro research has demonstrated that EMD promotes premature osteoblast clustering at early time points. The aim of the present study was to evaluate the influence of cell clustering on vital osteoblast cell-cell communication and adhesion molecules, connexin 43 (cx43) and N-cadherin (N-cad) as assessed by immunofluorescence imaging, real-time PCR and Western blot analysis. In addition, differentiation markers of osteoblasts were quantified using alkaline phosphatase, osteocalcin and von Kossa staining. EMD significantly increased the expression of connexin 43 and N-cadherin at early time points ranging from 2 to 5 days. Protein expression was localized to cell membranes when compared to control groups. Alkaline phosphatase activity was also significantly increased on EMD-coated samples at 3, 5 and 7 days post seeding. Interestingly, higher activity was localized to cell cluster regions. There was a 3 fold increase in osteocalcin and bone sialoprotein mRNA levels for osteoblasts cultured on EMD-coated culture dishes. Moreover, EMD significantly increased extracellular mineral deposition in cell clusters as assessed through von Kossa staining at 5, 7, 10 and 14 days post seeding. We conclude that EMD up-regulates the expression of vital osteoblast cell-cell communication and adhesion molecules, which enhances the differentiation and mineralization activity of osteoblasts. These findings provide further support for the clinical evidence that EMD increases the speed and quality of new bone formation in vivo

Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage

Osteoarthritis (OA) is a degenerative disease which causes pain and stiffness in joints. OA progresses through excessive degradation of joint cartilage, eventually leading to significant joint degeneration and loss of function. Cytokines, a group of cell signalling proteins, present in raised concentrations in OA joints, can be classified into pro-inflammatory and anti-inflammatory groups. They mediate cartilage degradation through several mechanisms, primarily the up-regulation of matrix metalloproteinases (MMPs), a group of collagen-degrading enzymes. In this paper we show that the interactions of cytokines within cartilage have a crucial role to play in OA progression and treatment. We develop a four-variable ordinary differential equation model for the interactions between pro- and anti-inflammatory cytokines, MMPs and fibronectin fragments (Fn-fs), a by-product of cartilage degradation and upregulator of cytokines. We show that the model has four classes of dynamic behaviour: homoeostasis, bistable inflammation, tristable inflammation and persistent inflammation. We show that positive and negative feedbacks controlling cytokine production rates can determine either a pre-disposition to OA or initiation of OA. Further, we show that manipulation of cytokine, MMP and Fn-fs levels can be used to treat OA, but we suggest that multiple treatment targets may be essential to halt or slow disease progression

Voices Raised, Issue 06

Included in this issue: Immaculate Mary; Grants augment women’s research; Mentoring grows; Women’s Studies take root in the neighborhood; Solution-oriented VP to retire; Muslim students strive to educate, support; Don’t let stress ruin your holidays; Dining services dishes up more than you’d expect; Marianist Images Across Campus; Confronting Disrespect: We Owe it to Each Other.https://ecommons.udayton.edu/wc_newsletter/1005/thumbnail.jp