Bone morphogenetic proteins in destructive and remodeling arthritis

Joint destruction and tissue responses determine the outcome of chronic arthritis. Joint inflammation and damage are often the dominant clinical presentation. However, in some arthritic diseases, in particular the spondyloarthritides, joint remodeling is a prominent feature, with new cartilage and bone formation leading to ankylosis and contributing to loss of function. A role for bone morphogenetic proteins in joint remodeling has been demonstrated in the formation of both enthesophytes and osteophytes. Data from genetic models support a role for bone morphogenetic protein signaling in cartilage homeostasis. Finally, this signaling pathway is likely to play a steering role in the synovium

Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis

Targeted therapies that neutralize tumour necrosis factor are often able to control the signs and symptoms of spondyloarthritis. However, recent animal model data and clinical observations indicate that control of inflammation may not be sufficient to impede disease progression toward ankylosis in these patients. Bone morphogenetic proteins and WNTs (wingless-type like) are likely to play an important role in ankylosis and could be therapeutic targets. The relationship between inflammation and new bone formation is still unclear. This review summarizes progress made in our understanding of ankylosis and offers an alternative view of the relationship between inflammation and ankylosis

Incorporating Quality In Engineered Tissues Using Bottom-Up Niche Assemblies

A major limitation in Tissue Engineering (TE) is the ability to control complexity within 3D engineered constructs. Diffusion limitations lead to the development of uncontrolled or even adverse environments leading to uncontrolled stem cell fate decision within the cultured tissue and cell death. Moreover the lack of control of the environment within these constructs makes the application of quality engineering principles such as quality by design (QbD) impossible. Length-scales chosen for the creation of in vitro tissues have not been chosen based on rational criteria and hence minimal success has been attained upon implantation. Recently bottom-up strategies have been introduced advocating the use of smaller tissue modules as building blocks for the formation of larger tissues prior to implantation. In this work we first cultured seeded human progenitor cells on non-adherent agarose surfaces containing microwells at their bottom, trapping the seeded cells, allowed initial condensations to take place and the formation of controlled-size aggregates (Figure 1A). After chondrogenic differentiation 3D cartilage intermediate µ-tissues where formed, positive for alcian blue and safranin-o stains indication the presence of mature cartilaginous extracellular matrix. These cartilaginous µ-tissues were fused via self-assembly for 24 hrs in vitro into larger implants with a diameter of 4 mm and implanted subcutaneously in small animal models. As control we used implants formed by progenitor cells cultured in pellet format in the same media formulation as the µ-tissues and containing the same amount of cells as the bottom-up assembled implant. Even at this scale a bone organ was formed in vivo containing a cortex and a bone marrow compartment while the macro-pellet demonstrated a large fibrotic tissue domain within the implant (Figure 1B, C). Please click Additional Files below to see the full abstract

Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane

We have demonstrated previously that adult human synovial membrane-derived mesenchymal stem cells (hSM-MSCs) have myogenic potential in vitro (De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten. 2001. Arthritis Rheum. 44:1928–1942). In the present study, we have characterized their myogenic differentiation in a nude mouse model of skeletal muscle regeneration and provide proof of principle of their potential use for muscle repair in the mdx mouse model of Duchenne muscular dystrophy. When implanted into regenerating nude mouse muscle, hSM-MSCs contributed to myofibers and to long term persisting functional satellite cells. No nuclear fusion hybrids were observed between donor human cells and host mouse muscle cells. Myogenic differentiation proceeded through a molecular cascade resembling embryonic muscle development. Differentiation was sensitive to environmental cues, since hSM-MSCs injected into the bloodstream engrafted in several tissues, but acquired the muscle phenotype only within skeletal muscle. When administered into dystrophic muscles of immunosuppressed mdx mice, hSM-MSCs restored sarcolemmal expression of dystrophin, reduced central nucleation, and rescued the expression of mouse mechano growth factor

Destructive Dural Ectasia of Dorsal and Lumbar Spine with Cauda Equina Syndrome in a Patient with Ankylosing Spondylitis

We present a patient with longstanding ankylosing spondylitis complicated with cauda equina syndrome. The patient suffered from increasing pain in the leg with reduced sensitivity and extremely cold feet associated with incontinence. Diagnostic workup revealed dural ectasia, arachnoiditis and a spinal inflammatory mass leading to extensive vertebral bone destruction. Of interest, this was not only found in the lumbar spine region (which is typical in cases of cauda equina syndrome associated with ankylosing spondylitis) but also in the lower cervical spine (C7) and upper dorsal spine. Moreover, the bone destructive phenotype of this complication of long-standing AS contrasts with the usual characteristics of new bone formation and ankylosis. As initial treatment with anti-inflammatory drugs was not sufficiently successful, infliximab therapy was started which resulted in manifest clinical improvement as chronic pain, incontinence and laboratory signs of inflammation progressively disappeared

Interactive visualization of cell expansion process performance

As cell-based technologies are rapidly evolving beyond the laboratory scale, the demand for mass production of high quality cells is increasing. Unfortunately, only limited amounts of cells can be sourced from (human) donors. Therefore sequences of cell expansion steps are required to multiply the original number of cells taken from the donor biopsy to the amounts required for clinical application. Currently a large variety of expansion processes are used and described in literature. However, it is extremely difficult to compare them as many mesenchymal stem cell (MSC) subtypes are used in different culture vessels, with different medium compositions, etc. Moreover, adding to this variation in expansion strategies, within one process there can be significant fluctuations in outcome due to process variability and inherent donor-to-donor related variability. The aim of this work was to analyze the performance of a range of expansion processes for large-scale MSC expansion. Therefore a literature-based study was performed, currently resulting in a database of 73 individual cell expansion processes in 5 different types of culture vessels (microcarrier, (layered) flasks, hollow fiber-, multiplate-, and packed bed-bioreactor), 6 different types of MSCs and many different media compositions. The scale of the processes in terms of final cell numbers ranged between 7.5x106 and 1.1x1010 cells. An interactive process map was created where the scale, efficiency, cell type, culture method and load on downstream processing can be explored (see figure below). This interactive visualization tool provides an integrated perspective on the different culture processes and is able to increase the understanding on process comparability, attainable cell yield, scale-up strategies and the effect of certain critical process parameters on the expansion result. Please click Additional Files below to see the full abstract

Subduction in the subtropical gyre : Seasoar cruises data report

The overall objective of the Subduction Accelerated Research Initiative (ARI) was to bring together several techniques to address the formation and evolution of newly formed water masses. The Seasoar component provided surveys of temperature and salinity to help determine the spatial varability of the temperature, salinity and density fields in both the active frontal regions and in the vicinity of subducting water tagged by bobbers. Data were collected in the eastern North Atlantic Ocean in spring 1991, winter 1992, winter 1993 and spring 1994. "Star" patterns were used to study the mesoscale varability. Temperature, pressure and thickness for each pattern were objectively mapped on potential density surfaces of 26.5, 26.7 and 26.9 kg/m3. Acoustic Doppler Current Profies (ADCP) maps were also created for the the two shallower density surfaces. We describe the Seasoar data collected during the four cruises. A CD-Rom includes 1- and 3-second conductivity-temperature-depth (CTD), cruise navigation, ADCP and Seasoar engineering data, as well as color figures of these data. This data report can also be viewed using an internet information browser (i.e., Mosaic, Netscape) using the provided CD-Rom.Funding was provided by the Office of Naval Research through Grants Nos, N00014-91-J-1585, N00014-90-J-1425. and N00014-90-J-1508

Noggin null allele mice exhibit a microform of holoprosencephaly

Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin−/− mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin−/− mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin−/− mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HP