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

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

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

Three dimensional characterization of tissue-engineered constructs by contrast enhanced nanofocus computed tomography.

peer reviewedIn order to successfully implement tissue engineered (TE) constructs as part of a clinical therapy, it is necessary to first develop and validate quality control tools that will ensure accurate and consistent TE construct release specifications. Hence advanced methods to monitor TE construct properties need to be further developed. In this study we showed proof of concept for contrast enhanced nanofocus computed tomography (CE-nanoCT) as a 'whole-construct' imaging technique with non-invasive potential that enables 3D visualization and quantification of in vitro engineered extracellular matrix (ECM) in TE constructs. In particular we performed a 3D quantitative and qualitative structural and spatial assessment of the in vitro engineered ECM, formed during static and perfusion bioreactor cell culture in 3D TE scaffolds, using two contrast agents, namely Hexabrix(R) and phosphotungstic acid (PTA). CE-nanoCT image data were validated by comparison to Live/Dead viability/cytotoxicity and picrosirius red staining data, and to the net dry weight of the TE constructs. When using Hexabrix(R) as contrast agent, ECM volume fitted linearly with net dry ECM weight independent from the flow rate used. When using PTA as contrast agent, CE-nanoCT data showed pronounced distinction between flow conditions when compared to both net dry weight and picrosirius red staining data although linearity was maintained, indicating culture-specific structural ECM differences. This was attributed to the binding specificity of this contrast agent. This novel type of information can contribute to optimize bioreactor culture conditions and potentially critical quality characteristics of TE constructs such as ECM quantity and homogeneity, facilitating the gradual transformation of 'TE constructs' in well characterized 'TE products'.I.P. is funded by the ENDEAVOUR project G.0982.11N of the FWO;M.S. is supported by a Ph.D. grant of the Agency for Innovation by Science and Technology (IWT/111457). G.K. and L.G. acknowledge support by the European Research Council under the European Union's Seventh Framework Program (FP7/2007–2013)/ERC grant agreement n°279100

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