The proposed synovitis score is based on well-defined, reproducible histopathological criteria and may contribute to diagnosis in rheumatic and non-rheumatic joint diseases.

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We previously identified multipotent stem cells within the lamina propria of the human olfactory mucosa, located in the nasal cavity. We also demonstrated that this cell type differentiates into neural cells and improves locomotor behavior after transplantation in a rat model of Parkinson's disease. Yet, next to nothing is known about their specific stemness characteristics. We therefore devised a study aiming to compare olfactory lamina propria stem cells from 4 individuals to bone marrow mesenchymal stem cells from 4 age- and gender-matched individuals. Using pangenomic microarrays and immunostaining with 34 cell surface marker antibodies, we show here that olfactory stem cells are closely related to bone marrow stem cells. However, olfactory stem cells also exhibit singular traits. By means of techniques such as proliferation assay, cDNA microarrays, RT-PCR, in vitro and in vivo differentiation, we report that when compared to bone marrow stem cells, olfactory stem cells display (1) a high proliferation rate; (2) a propensity to differentiate into osseous cells; and (3) a disinclination to give rise to chondrocytes and adipocytes. Since peripheral olfactory stem cells originate from a neural crest-derived tissue and, as shown here, exhibit an increased expression of neural cell-related genes, we propose to name them olfactory ectomesenchymal stem cells (OE-MSC). Further studies are now required to corroborate the therapeutic potential of OE-MSCs in animal models of bone and brain diseases.

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We have studied the plasma membrane protein phenotype of human cultureamplified and native bone marrow mesenchymal stem cells (BM MSCs). We have found, using microarrays and flow cytom-

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Objective. Anti-citrullinated protein antibodies (ACPA) exhibit unique specificity for rheumatoid arthritis. However, it is incompletely understood whether and how ACPA contribute to disease pathogenesis. The Fc part of human IgG carries 2 N-linked glycan moieties that are crucial for the structural stability of the antibody and that modulate both its binding affinity to Fc␥ receptors and its ability to activate complement. We undertook this study to analyze Fc glycosylation of IgG1 ACPA in serum and synovial fluid (SF) in order to further characterize the immune response to citrullinated antigens.Methods. ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. IgG1 Fc glycosylation was analyzed by mass spectrometry. ACPA IgG1 glycan profiles were compared with glycan profiles of total serum IgG1 obtained from 85 wellcharacterized patients. Glycan profiles of paired SF and serum samples were available from 11 additional patients.Results. Compared with the pool of serum IgG1, ACPA IgG1 lacked terminal sialic acid residues. In SF, ACPA were highly agalactosylated and lacked sialic acid residues, a feature that was not detected for total SF IgG1. Moreover, differential ACPA glycan profiles were detected in rheumatoid factor (RF)-positive and RFnegative patients.Conclusion. ACPA IgG1 exhibit a specific Fclinked glycan profile that is distinct from that of total serum IgG1. Moreover, Fc glycosylation of ACPA differs markedly between SF and serum. Since Fc glycosylation directly affects the recruitment of Fc-mediated effector mechanisms, these data could further our understanding of the contribution of ACPA to disease pathogenesis.Antibodies relevant to tissue pathology in autoimmune diseases are identified based on antigen-binding specificity of the variable region. Only very few autoantibodies, however, mediate pathology by direct interaction with the antigen. In most other cases, the constant region (Fc part) determines antibody-mediated effector functions, such as complement activation, antibodydependent cell-mediated cytotoxicity (ADCC), and engagement of activating or inhibitory Fc receptors (FcR). These Fc-mediated effects are influenced by the amino acid sequence of the Fc part (i.e., antibody isotype and subclass) and by Fc-linked carbohydrate structures. The latter are located in the C␥2 domain of the heavy chain in close proximity to amino acids that interact with FcR and the complement system. Accordingly, Fc-linked carbohydrate structures have recently received increasing attention, since modification of Fc-linked glycan residues of therapeutic antibodies has been shown to strongly influence the therapeutic potential of the antibodies (1-6).

Adult human mesenchymal stromal cells (hMSCs) have the potential to differentiate into chondrogenic, adipogenic, or osteogenic lineages, providing a potential source for tissue regeneration. An important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptome analysis, we found that integrin ␣5 (ITGA5) expression is up-regulated during dexamethasone-induced osteoblast differentiation of hMSCs. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers and in vitro osteogenesis of hMSCs. Down-regulation of endogenous ITGA5 using specific shRNAs blunted osteoblast marker gene expression and osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by ITGA5 was mediated by activation of focal adhesion kinase/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of endogenous ITGA5 using agonists such as a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. Importantly, we demonstrated that hMSCs engineered to overexpress ITGA5 exhibited a marked increase in their osteogenic potential in vivo. Taken together, these findings not only reveal that ITGA5 is required for osteoblast differentiation of adult hMSCs but also provide a targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs. This may be used for tissue regeneration in bone disorders where the recruitment or capacity of hMSCs is compromised. mesenchymal stem cells ͉ bone formation ͉ agonist M esenchymal stromal cells (MSCs) derived from the bone marrow stroma are capable of differentiating into chondroblasts, adipocytes, or osteoblasts (1, 2) under appropriate environmental conditions (3, 4). Adult human MSCs (hMSCs) are considered as a valuable source for bone tissue regeneration in human diseases (5, 6). However, the capacity of autologous hMSCs to differentiate along functional bone-forming osteoblasts remains relatively limited for bone regeneration in vivo (7). An important issue for efficient bone regeneration is therefore to target hMSCs to promote their osteogenic potential for in vivo bone regeneration.The osteogenic differentiation process of MSCs is characterized by the expression of the main osteoblast transcription factor Runx2 and osteoblast markers such as alkaline phosphatase (ALP) and type I collagen (Col1A1) and is typified by ECM mineralization (8-10). The ECM-osteoblast interactions generate important signaling mechanisms that converge to promote early osteoblast-specific gene expression and differentiation (11-13). Cell-matrix interactions involve integrins, a family of transmembrane proteins that induce intracellular signals (14,15). The ␣5␤1 integrin is a cell surface receptor for fibronectin that has been implicated in cell spreading, proliferation, di...