Toward defining the role of the synovium in mitigating normal articular cartilage wear and tear.

Cartilage repair has been studied extensively in the context of injury and disease, but the joint's management of regular sub-injurious damage to cartilage, or 'wear and tear,' which occurs due to normal activity, is poorly understood. We hypothesize that this cartilage maintenance is mediated in part by cells derived from the synovium that migrate to the worn articular surface. Here, we demonstrate in vitro that the early steps required for such a process can occur. First, we show that under physiologic mechanical loads, chondrocyte death occurs in the cartilage superficial zone along with changes to the cartilage surface topography. Second, we show that synoviocytes are released from the synovial lining under physiologic loads and attach to worn cartilage. Third, we show that synoviocytes parachuted onto a simulated or native cartilage surface will modify their behavior. Specifically, we show that synoviocyte interactions with chondrocytes lead to changes in synoviocyte mechanosensitivity, and we demonstrate that cartilage-attached synoviocytes can express COL2A1, a hallmark of the chondrogenic phenotype. Our findings suggest that synoviocyte-mediated repair of cartilage 'wear and tear' as a component of joint homeostasis is feasible and is deserving of future study.

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints - Therapeutic Targets in Post-Traumatic Osteoarthritis?

Synovial joints are complex structures that enable normal locomotion. Following injury, they undergo a series of changes, including a prevalent inflammatory response. This increases the risk for development of osteoarthritis (OA), the most common joint disorder. In healthy joints, macrophages are the predominant immune cells. They regulate bone turnover, constantly scavenge debris from the joint cavity and, together with synovial fibroblasts, form a protective barrier. Macrophages thus work in concert with the non-hematopoietic stroma. In turn, the stroma provides a scaffold as well as molecular signals for macrophage survival and functional imprinting: "a macrophage niche". These intricate cellular interactions are susceptible to perturbations like those induced by joint injury. With this review, we explore how the concepts of local tissue niches apply to synovial joints. We introduce the joint micro-anatomy and cellular players, and discuss their potential interactions in healthy joints, with an emphasis on molecular cues underlying their crosstalk and relevance to joint functionality. We then consider how these interactions are perturbed by joint injury and how they may contribute to OA pathogenesis. We conclude by discussing how understanding these changes might help identify novel therapeutic avenues with the potential of restoring joint function and reducing post-traumatic OA risk.

Efficacy of Combination Therapy with Apigenin and Synovial Membrane-Derived Mesenchymal Stem Cells on Knee Joint Osteoarthritis in a Rat Model.

Background: Osteoarthritis (OA) is a degenerative joint disease that causes a variety of adverse health effects. Considering the need to identify additional effective therapeutic options for OA therapy, we investigated the effect of co-injection of apigenin and synovial membrane-derived mesenchymal stem cells (SMMSCs) on OA in male rats' knee joints. Methods: The study was performed in 2019 at the Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran. Anterior cruciate ligament transection (ACLT) was used to induce OA. For three weeks, male Sprague-Dawley rats (eight groups, n=6 each) were treated once-weekly with intra-articular injections of apigenin alone or in combination with SMMSC (three million cells), phosphate-buffered saline, or hyaluronic acid. After three months, the interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the cartilage homogenate. The expression of extracellular matrix (ECM) components including collagen 2a1, aggrecan, IL-1ß, TNF-α, inducible nitric oxide synthase (iNOS), transcription factor SOX-9, and matrix metalloproteinases 3 and 13 were assessed using real-time polymerase chain reaction (RT-PCR) analysis. Radiological evaluation and histopathological assessment were used to evaluate the knees. Results: Levels of TNF-α (P=0.009), MDA (P>0.001), and IL-1ß (P<0.001) decreased and the level of SOD increased (P=0.004) in the apigenin 0.3 µM with SMMSCs group. RT-PCR analysis indicated that IL-1ß in the apigenin 0.3 µM with SMMSCs group reduced significantly (P<0.001). This group also exhibited increased expression levels of SOX-9, collagen 2a1, and aggrecan (P<0.001). Conclusion: Apigenin may have supplementary beneficial effects on cell therapy in a rat model of OA due to its possible effect on the reduction of oxidative stress, suppression of inflammation, and promotion of production of ECM components.

Identification of Novel Targets of Knee Osteoarthritis Shared by Cartilage and Synovial Tissue.

Arthritis is the leading cause of disability among adults, while osteoarthritis (OA) is the most common form of arthritis that results in cartilage loss. However, accumulating evidence suggests that the protective hyaline cartilage should not be the sole focus of OA treatment. Particularly, synovium also plays essential roles in OA's initiation and progression and warrants serious consideration when battling against OA. Thus, biomarkers with similar OA-responsive expressions in cartilage and synovium should be the potential targets for OA treatment. On the other hand, molecules with a distinguished response during OA in cartilage and synovium should be ruled out as OA therapeutic(s) to avoid controversial effects in different tissues. Here, to pave the path for developing a new generation of OA therapeutics, two published transcriptome datasets of knee articular cartilage and synovium were analyzed in-depth. Genes with statistically significantly different expression in OA and healthy cartilage were compared with those in the synovium. Thirty-five genes with similar OA-responsive expression in both tissues were identified while recognizing three genes with opposite OA-responsive alteration trends in cartilage and synovium. These genes were clustered based on the currently available knowledge, and the potential impacts of these clusters in OA were explored.

TLRs Play Crucial Roles in Regulating RA Synoviocyte.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes (synoviocytes) are crucial ingredients of synovium. Therein, a lot of research has focused on synoviocytes. Researches demonstrated that TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 TLR7 and TLR9 are expressed in synoviocyte. Additionally, the expression of TLR2, TLR3, TLR4 and TLR5 is increased in RA synoviocyte. In this paper, we review the exact role of TLR2, TLR3, TLR4 and TLR5 participate in regulating the production of inflammatory factors in RA synoviocyte. Furthermore, we discuss the role of vasoactive intestinal peptide (VIP), MicroRNA, Monome of Chinese herb and other cells (Monocyte and T cell) influence the function of synoviocyte by regulating TLRs. The activation of toll-like receptors (TLRs) in synoviocyte leads to the aggravation of arthritis, comparing with angiogenesis and bone destruction. Above all, TLRs are promising targets for managing RA.

Cruciate ligament healing and injury prevention in the age of regenerative medicine and technostress: homeostasis revisited.

PURPOSE: This clinical concepts paper discusses the essential elements of cruciate ligament recuperation, micro-trauma repair, and remodeling. METHODS: Cruciate ligament mechanobiology and tissue heterogeneity, anatomy and vascularity, and synovial membrane and fluid functions are discussed in relationship to deficiency-induced inflammatory responses, nervous and immune system function, recuperation, repair and remodeling, and modern threats to homeostasis. RESULTS: Cruciate ligament surgical procedures do not appreciate the vital linked functions of the central, peripheral, and autonomic nervous systems and immune system function on knee ligament injury recuperation, micro-trauma repair, and remodeling. Enhanced knowledge of these systems could provide innovative ways to decrease primary non-contact knee injury rates and improve outcomes following reconstruction or primary repair. CONCLUSIONS: Restoration of knee joint homeostasis is essential to cruciate ligament recuperation, micro-trauma repair, and remodeling. The nervous and immune systems are intricately involved in this process. Varying combinations of high-intensity training, under-recovery, technostress, and environmental pollutants (including noise) regularly expose many athletically active individuals to factors that abrogate the environment needed for cruciate ligament recuperation, micro-trauma repair, and remodeling. Current sports training practice, lifestyle psychobehaviors, and environmental factors combine to increase both primary non-contact knee injury risk and the nervous and immune system dysregulation that lead to poor sleep, increased anxiety, and poorly regulated hormone and cytokine levels. These factors may create a worst-case scenario leading to poor ligament recuperation, micro-trauma repair, and remodeling. Early recognition and modification of these factors may decrease knee ligament injury rates and improve cruciate ligament repair or reconstruction outcomes. LEVEL OF EVIDENCE: V.

Recent findings regarding the effects of microRNAs on fibroblast-like synovial cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with severe joint inflammation and destruction characterized by marked hyperplasia of the lining layer of the synovium. Fibroblast-like synovial cells (FLS) is a key cellular component within the synovia; it plays pivotal roles in RA pathogenesis by unfavorable behaviors such as producing inflammatory cytokines and chemokines, and hyperproliferation. MicroRNAs are evolutionarily conserved small non-coding RNAs (length is 18-25 nucleotides) that regulate gene expression at the post-transcriptional level. There is increasing interest in the involvement of microRNAs in autoimmune diseases including RA. Recent studies revealed the regulation of the function of FLS by microRNAs. Here, we review the known functional microRNAs in RA and summarize the potential uses of these small molecules in the treatment of RA.

Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis?

The synovium exercises its main function in joint homeostasis through the secretion of factors (such as lubricin and hyaluronic acid) that are critical for the joint lubrication and function. The main synovium cell components are fibroblast-like synoviocytes, mesenchymal stromal/stem cells and macrophage-like synovial cells. In the synovium, cells of mesenchymal origin modulate local inflammation and fibrosis, and interact with different fibroblast subtypes and with resident macrophages. In pathologic conditions, such as rheumatoid arthritis, fibroblast-like synoviocytes proliferate abnormally, recruit mesenchymal stem cells from subchondral bone marrow, and influence immune cell activity through epigenetic and metabolic adaptations. The resulting synovial hyperplasia leads to secondary cartilage destruction, joint swelling, and pain. In the present review, we summarize recent findings on the molecular signature and the roles of stromal cells during synovial pannus formation and rheumatoid arthritis progression.

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis.

BACKGROUND Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. MATERIAL AND METHODS Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. RESULTS DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. CONCLUSIONS The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.

Multiple mesenchymal progenitor cell subtypes with distinct functional potential are present within the intimal layer of the hip synovium.

BACKGROUND: The synovial membrane adjacent to the articular cartilage is home to synovial mesenchymal progenitor cell (sMPC) populations that have the ability to undergo chondrogenesis. While it has been hypothesized that multiple subtypes of stem and progenitor cells exist in vivo, there is little evidence supporting this hypothesis in human tissues. Furthermore, in most of the published literature on this topic, the cells are cultured before derivation of clonal populations. This gap in the literature makes it difficult to determine if there are distinct MPC subtypes in human synovial tissues, and if so, if these sMPCs express any markers in vivo/in situ that provide information in regards to the function of specific MPC subtypes (e.g. cells with increased chondrogenic capacity)? Therefore, the current study was undertaken to determine if any of the classical MPC cell surface markers provide insight into the differentiation capacity of sMPCs. METHODS: Clonal populations of sMPCs were derived from a cohort of patients with hip osteoarthritis (OA) and patients at high risk to develop OA using indexed cell sorting. Tri-differentiation potential and cell surface receptor expression of the resultant clones was determined. RESULTS: A number of clones with distinct differentiation potential were derived from this cohort, yet the most common cell surface marker profile on MPCs (in situ) that demonstrated chondrogenic potential was determined to be CD90+/CD44+/CD73+. A validation cohort was employed to isolate cells with only this cell surface profile. Isolating cells directly from human synovial tissue with these three markers alone, did not enrich for cells with chondrogenic capacity. CONCLUSIONS: Therefore, additional markers are required to further discriminate the heterogeneous subtypes of MPCs and identify sMPCs with functional properties that are believed to be advantageous for clinical application.

miR-125 regulates PI3K/Akt/mTOR signaling pathway in rheumatoid arthritis rats via PARP2.

The present study aimed to explore miR-125 effects on rheumatoid arthritis (RA) development to provide a potential target for RA. Briefly, rat RA model was established (Model group) by injection of Freund's Complete Adjuvant into the left hind toe. Normal rats injected with saline in the same location were set as Normal group. All rats' secondary foot swelling degree, polyarthritis index score, spleen and thymus index were measured. Synovial tissues were subjected to Hematoxylin-Eosin (HE) staining and immunohistochemistry. Synovial cells of each group were isolated and named as Normal-C group and Model-C group, respectively. Synovial cells of Model-C group further underwent cotransfection with miR-125 mimics and PARP2-siRNA (mimics+siPARP2 group) or with miR-125 negative control (NC) and PARP2-siRNA NC (NC group). Quantitative reverse transcriptase PCR (qRT-PCR), Western blot, luciferase reporter assay, ELISA, and MTT assay were performed. As a result, compared with Normal group, rats of Model group showed significantly higher secondary foot swelling degree, polyarthritis index score, spleen and thymus index (P<0.01). Down-regulated miR-125 and up-regulated PARP2 was found in synovial tissues of Model group when compared with Normal group (P<0.01). Synovial tissues of Model-C group exhibited severe hyperplasia and inflammatory cell infiltration. Luciferase reporter assay indicated that PARP2 was directly inhibited by miR-125. Compared with NC group, cells of mimics+siPARP2 group had significantly lower IL-1ß, MMP-1 and TIMP-1 levels, absorbance value, and p-PI3K, p-Akt and p-mTOR relative expression (P<0.01 or P<0.05). Thus, miR-125 might attenuate RA development by regulating PI3K/Akt/mTOR signaling pathway via directly inhibiting PARP2 expression.

Synovial hemangiomas of wrist and ankle joint: A report of two rare cases.

Synovial hemangioma is a rare, benign, vascular tumor of synovium leading to joint pain and swelling. The most common site is the knee joint, but rare cases involving other sites have also been reported. We report two rare cases of synovial hemangioma, one involving the ankle joint and other involving the wrist joint. Histopathology is the gold standard for diagnosis of these cases. Early treatment is warranted to prevent the risk of permanent joint damage.

Comparison of mesenchymal stem cells obtained by suspended culture of synovium from patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Mobilization of mesenchymal stem cells (MSCs) from the synovium was revealed using a "suspended synovium culture model" of osteoarthritis (OA). The pathology of rheumatoid arthritis (RA) differs from that of OA. We investigated whether mobilization of MSCs from the synovium also occurred in RA, and we compared the properties of synovial MSCs collected from suspended synovium culture models of RA and OA. METHODS: Human synovium was harvested during total knee arthroplasty from the knee joints of patients with RA (n = 8) and OA (n = 6). The synovium was suspended in a bottle containing culture medium and a culture dish at the bottom. Cells were harvested from the dish and analyzed. RESULTS: No significant difference was observed between RA and OA in the harvested cell numbers per g of synovium. However, the variation in the number of cells harvested from each donor was greater for RA than for OA. The harvested cells were multipotent and no difference was observed in the cartilage pellet weight between RA and OA. The surface epitopes of the cells in RA and OA were similar to those of MSCs. CONCLUSION: Mobilization of MSCs from the synovium was demonstrated using a suspended synovium culture model for RA. The harvested cell numbers, chondrogenic potentials, and surface epitope profiles were comparable between the RA and OA models.

Hsa_circ_0001859 Regulates ATF2 Expression by Functioning as an MiR-204/211 Sponge in Human Rheumatoid Arthritis.

BACKGROUND: circRNAs are part of the competitive endogenous RNA network, which putatively function as miRNA sponges and play a crucial role in the development of numerous diseases. However, studies of circRNAs in rheumatoid arthritis (RA) disease are limited. This work aims to identify the expression pattern of circRNAs in synovial tissues and their inflammatory regulation mechanism. METHODS: We first compared the mRNA expression in rheumatoid arthritis patients with that in healthy volunteers by GEO database mining to identify gene loci specifically expressed in synovial tissues. Functional enrichment algorithms were then used to draw the interactome diagram of circRNAs-miRNAs-mRNAs. Finally, loss-of-function and rescue assays of the candidate circRNAs were performed in vitro. RESULTS: A total of 29 differentially expressed circRNAs related to rheumatoid arthritis were discovered. Silencing of hsa_circ_0001859 suppressed ATF2 expression and decreased inflammatory activity in SW982 cells. Hsa_circ_0001859 could compete with ATF2 for miR-204/211. DISCUSSION: These findings indicate that hsa_circ_0001859 participates deeply in the process of chronic inflammatory disease in synovial tissue.

Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives.

Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed.

Meniscal regeneration after resection of the anterior half of the medial meniscus in mice.

Various animal studies have indicated that reduced meniscal function significantly exacerbates articular-cartilage degeneration. Despite the importance of meniscal function for joint homeostasis and prevention of osteoarthritis, the healing process after meniscal injury and the regenerative process after meniscus removal have not been studied in detail. In this study, we examined the process of meniscal regeneration and cartilage degeneration after meniscectomy in mice. The left anterior halves of the medial menisci in male C57Bl/6J mice were resected, and histological assessment of the process of meniscal regeneration was conducted on day 3 and 2, 4, and 6 weeks after the surgical procedure. Extensive macrophagic infiltration into the synovial membrane around the meniscectomized area was observed on day 3. Synovial hyperplasia was detected 2 weeks after the operation. At this stage, synovial tissue was filled with many fibroblastic cells, which underwent chondrocytic differentiation and produced cartilage matrices by 4 weeks after the operation. At 6 weeks, regenerated tissues resembled those of an intact meniscus. The articular cartilage at the interface of the resected meniscus significantly degenerated between 2 and 4 weeks after the surgical procedure, but subtle progression in cartilage degeneration was observed between 4 and 6 weeks. This finding is suggestive of a balance between meniscal regeneration and cartilage homeostasis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1958-1965, 2017.

Cartilage damage and bone erosion are more prominent determinants of functional impairment in longstanding experimental arthritis than synovial inflammation.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 - the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model.

Nerve Growth Factor Regulation by TNF-α and IL-1ß in Synovial Macrophages and Fibroblasts in Osteoarthritic Mice.

To investigate the role of macrophages as a regulator and producer of nerve growth factor (NGF) in the synovial tissue (ST) of osteoarthritis (OA) joints, the gene expression profiles of several inflammatory cytokines in the ST, including synovial macrophages and fibroblasts, of OA mice (STR/Ort) were characterized. Specifically, real-time polymerase chain reaction analysis was used to evaluate the expression of tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1ß, IL-6, and NGF in CD11b+ and CD11b- cells isolated from the ST of a murine OA model. The effects of TNF-α, IL-1ß, and IL-6 on the expression of NGF in cultured synovial cells were also examined. The expression of TNF-α, IL-1ß, IL-6, and NGF in the ST of STR/Ort was higher than that in C57/BL6J mice. Compared to the CD11b- cell fraction, higher expression levels of TNF-α, IL-1ß, and IL-6 were detected in the CD11b+ cell fraction, whereas no differences in the expression of NGF were detected between the two cell fractions. Notably, TNF-α upregulated NGF expression in synovial fibroblasts and macrophages and IL-1ß upregulated NGF expression in synovial fibroblasts. IL-1ß and TNF-α may regulate NGF signaling in OA joints and be suitable therapeutic targets for treating OA pain.

Validity and sensitivity to change of the semi-quantitative OMERACT ultrasound scoring system for tenosynovitis in patients with rheumatoid arthritis.

OBJECTIVES: The aim was to evaluate the metric properties of the semi-quantitative OMERACT US scoring system vs a novel quantitative US scoring system for tenosynovitis, by testing its intra- and inter-reader reliability, sensitivity to change and comparison with clinical tenosynovitis scoring in a 6-month follow-up study. METHODS: US and clinical assessments of the tendon sheaths of the clinically most affected hand and foot were performed at baseline, 3 and 6 months in 51 patients with RA. Tenosynovitis was assessed using the semi-quantitative scoring system (0-3) proposed by the OMERACT US group and a new quantitative US evaluation (0-100). A sum for US grey scale (GS), colour Doppler (CD) and pixel index (PI), respectively, was calculated for each patient. In 20 patients, intra- and inter-observer agreement was established between two independent investigators. A binary clinical tenosynovitis score was performed, calculating a sum score per patient. RESULTS: The intra- and inter-observer agreements for US tenosynovitis assessments were very good at baseline and for change for GS and CD, but less good for PI. The smallest detectable change was 0.97 for GS, 0.93 for CD and 30.1 for PI. The sensitivity to change from month 0 to 6 was high for GS and CD, and slightly higher than for clinical tenosynovitis score and PI. CONCLUSION: This study demonstrated an excellent intra- and inter-reader agreement between two investigators for the OMERACT US scoring system for tenosynovitis and a high ability to detect changes over time. Quantitative assessment by PI did not add further information.

CD105 promotes chondrogenesis of synovium-derived mesenchymal stem cells through Smad2 signaling.

Mesenchymal stem cells (MSCs) are considered to be suitable for cell-based tissue regeneration. Expressions of different cell surface markers confer distinct differentiation potential to different sub-populations of MSCs. Understanding the effect of cell surface markers on MSC differentiation is essential to their targeted application in different tissues. Although CD105 positive MSCs possess strong chondrogenic capacity, the underlying mechanisms are not clear. In this study, we observed a considerable heterogeneity with respect to CD105 expression among MSCs isolated from synovium. The CD105(+) and CD105(-) synovium-derived MSCs (SMSCs) were sorted to compare their differentiation capacities and relative gene expressions. CD105(+) subpopulation had higher gene expressions of AGG, COL II and Sox9, and showed a stronger affinity for Alcian blue and immunofluorescent staining for aggrecan and collagenase II, as compared to those in CD105(-) cells. However, no significant difference was observed with respect to gene expressions of ALP, Runx2, LPL and PPARγ. CD105(+) SMSCs showed increased levels of Smad2 phosphorylation, while total Smad2 levels were similar between the two groups. There was no difference in activation of Smad1/5. These results were further confirmed by CD105-knockdown in SMSCs. Our findings suggest a stronger chondrogenic potential of CD105(+) SMSCs in comparison to that of CD105(-) SMSCs and that CD105 enhances chondrogenesis of SMSCs by regulating TGF-ß/Smad2 signaling pathway, but not Smad1/5. Our study provides a better understanding of CD105 with respect to chondrogenic differentiation.