Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis
© Mohanty et al.; licensee BioMed Central Ltd. 2010
Received: 8 April 2010
Accepted: 22 July 2010
Published: 22 July 2010
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment.
We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease.
We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss.
Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic disruptive polyarthritis. There is no cure for RA and today's treatments aim at achieving the lowest possible level of arthritis disease activity. In the UK alone RA costs the health system around £560 million a year, and £1.8 billion a year in absence from work. The events preceding the disease and leading to its initiation and progression are unknown. Thus, an understanding of these processes is crucial for the identification of new and more cost-effective treatments and for the move from a manageable to a curable disease.
Although the main disease site is the synovium, there is growing evidence that the bone marrow (BM) is actively involved and may even be the primary initiating site of the disease . Abnormalities in both the haemopoietic progenitor cells and the BM stroma have been described . Patients with active RA have been seen to exhibit low frequency and accelerated apoptosis of BM CD34+ cells and defective clonogenic potential . Difficulties in haemopoietic stem cell (HSC) transplantation with very common, but unfortunately, relatively short-lived responses have been reported . Moreover, age-inappropriate shortening of telomeres in CD4 T cells and granulocytes have been shown not only in patients affected by RA but also in healthy adult HLA-DR4 donors, the HLA haplotype with the major genetic risk factor for RA . These data suggest that HSC undergo increased replicative stress not only in patients affected by RA but also in patients predisposed to RA and it can occur independently of the rheumatoid disease process. The causes of the increased apoptosis and replicative stress of HSC in patients affected by RA are unknown.
HSC requires a balanced supportive environment, the niche, to survive, proliferate and appropriately differentiate. An impaired hematopoiesis-supporting capacity of BM stroma has been described in RA patients . However, it is unknown what the changes are in the bone marrow (BM) niche, which may lead to ineffective support of HSC. Mesenchymal stem cells (MSCs), and their differentiated progenies, including osteoblasts and adipocytes, have been shown to be important elements of the BM niche and have a role in HSC survival, proliferation and differentiation [5–8]. Cells with properties of MSC have been found to increase in the synovium of patients affected by RA and are thought to be one of the main causes of perpetuation of the disease, suggesting a possible dysregulation of MSC proliferative capacity . In this study, we hypothesize that bone marrow MSCs undergo enhanced self-renewal at the onset of RA-like disease.
To test this hypothesis we have used an Interleukin-1 receptor antagonist knock out mouse model of RA on a Balb/c background (Balb/c IL1ra-/-), which spontaneously develops inflammatory arthropathy with inflammatory cellular infiltration, pannus formation and periarticular bone erosions, similar to RA in humans, with 100% penetrance by weeks 20 of age . We have determined the changes present in the bone marrow microenvironment before disease onset and with development of RA-like disease.
This study showed the presence of important changes occurring in the bone marrow niche before disease onset in relation to mesenchymal progenitors, adipogenesis and osteoclastogenesis. It identifies progressive amplification of mesenchymal progenitors in the bone marrow with disease onset and progression but impairment of their differentiation to the osteogenic lineage.
Materials and methods
Reagents and animals
Balb/c and C57BL6 Interleukin-1 receptor antagonist knock-out mice (Balb/c IL-1ra-/- and C57Bl/6 IL1ra-/- respectively) and age-matched wild type (WT) controls were used for the experiments. All animal procedures were conducted in compliance with institutional and national guidelines and with ethics committee approval (PPL 40/2655). Balb/c IL-1ra-/- mice spontaneously develop chronic inflammatory arthropathy that closely resembles RA in humans . IL-1ra-/- mice were monitored by visual inspection and mice were sacrificed a) before disease onset; b) at disease onset identified by the first visual appearance of swelling and redness of joints; or c) late disease, characterized by persistent disease (five weeks from the first sight of joint swelling). In contrast C57BL6 IL1 ra-/- do not develop any inflammatory arthropathy  and were used as a further control group. Bone marrow cells (BMCs) were flushed from the long bones of mice and used for progenitor assays. Tibiae were dissected from soft tissue and used for microCT and histomorphometric analysis.
Progenitor cell assays
Colony Forming Unit-Fibroblasts (CFU-F)
BMCs were plated at the densities of 5 × 105 and 106 cells per well in duplicate in murine-mesenchymal stem cell complete medium (Stem Cell Technologies, Vancouver, Canada). The plates were incubated for 14 days at 37°C in 5% CO2 in air. Colonies were visualized by Giemsa's stain solution (VWR, Leicestershire, UK). Colonies with a minimum of 50 cells were considered as one CFU-F.
Colony Forming Unit-Osteoblast (CFU-O)
BMCs were plated at a density of 5 × 105 and 106 cells per well in duplicate in Dulbecco's modified Eagle medium (DMEM) plus 10% fetal calf serum (FCS) supplemented with 100 nM dexamethasone (Sigma Aldrich, St. Louis, MO, USA), 10 mM β glycerophosphate (Sigma Aldrich) and 0.05 mM L-Ascorbic Acid (Sigma Aldrich). Cells were maintained in culture for 14 days and fed twice a week. Cells were stained for alkaline phosphatase (ALP) activity using the 86 R alkaline phosphatase kit (Sigma Aldrich). The colonies comprising at least 20 cells positive for ALP were considered as one CFU-O.
Colony Forming Unit-Adipocyte (CFU-A) by limiting dilution analysis
BMCs were plated at limiting dilutions (range 105 to 6.25 × 103 cells, eight wells/dilution) in DMEM plus 10% FCS (Hyclone, Fisher Scientific, Loughborough, UK) in a 96-well culture plate and fed twice a week for two weeks. After two weeks cultures were supplemented with Rosiglitazone (5 μM) and cultured at 37°C in CO2 in air for two more weeks. To detect lipid vacuoles cultures were stained for Oil red O as previously described . This method follows the Poisson distribution and measures the abundance of cells able to perform a particular function, in this case to become adipocytes. A well is considered positive if it contains more than 20 cells with red lipid vacuoles. The number of CFU-A was calculated using the formula Fo = e-x, where Fo is the fraction of colony-negative wells, e is the constant whose value is 2.71 and x is the number of colony forming units per well .
Micro computed tomography (CT)
The tibiae were scanned using a microCT scanner (model 1172, Skyscan, Aartselaar, Belgium) at 50 kV and 200 μA with a 0.5 aluminium filter using a detection pixel size of 4.3 μm. Images were captured every 0.7° through 180° rotation of the bone. The scanned images were reconstructed using the Skyscan Recon software and analysed using Skyscan CT analysis software. A standard trabecular bone volume of interest was chosen starting 0.2 mm from the growth plate and included all the trabeculae in 1 mm3 of bone.
Tibiae were fixed in 10% neutral buffered formalin, decalcified in EDTA, and embedded in paraffin, and 3 μm sections were cut using a Leica Microsystems microtome (Leica Microsystems, Milton Keynes, UK). The sections were stained with either Hematoxylin and Eosin or Tartrate Resistant Acid Phosphatise (TRAP) to identify osteoclasts and counterstained with Gill's hematoxylin. The sections were examined by light microscopy (Leica Microsystems). The number of osteoblasts and osteoclasts per millimeter were measured on 6.5 mm of the corticoendosteal surfaces, starting 0.25 mm from the growth plate using the Osteomeasure analysis software (Osteometrics, Decatur, GA, USA). Bone marrow adiposity was determined by measuring the area occupied by the adipocytes recognised as white holes defined by the light blue staining cell wall over 0.75 mm2.
All experiments were analyzed using a t-test or a one-way ANOVA-Dunnett's post test for multiple comparisons. All results are expressed as the mean ± SEM. Significant P-values were less than 0.05.
Decreased number of bone marrow progenitors with adipogenic potential and bone marrow adiposity precedes the onset of RA disease
To determine if the decrease in mesenchymal progenitors with adipogenic potential resulted in a decrease in bone marrow adiposity, the percentage of bone marrow area occupied by adipocytes was determined in Balb/c IL1ra-/- and compared to age matched wild type controls (age 6 to 14 weeks). As expected this was significantly reduced (Figure 1d, n = 9, P = 0.02).
Decreased numbers of activated osteoclasts precede the onset of RA disease
Bone marrow mesenchymal progenitors increase in numbers with onset and progression of disease
Block in osteoblast differentiation with disease progression
As osteoclasts were significantly decreased in Balb/c IL1ra-/- before the start of RA-like arthritis and they are known to be increasingly activated in the joint of patients affected by RA we determined whether the number of activated osteoclasts was affected by the disease onset and progression. No significant difference in osteoclasts numbers was found at disease onset (1.3 ± 0.2 vs 1 ± 0.3 N Oc/mm, WT vs Balb/c IL1ra-/- respectively n = 6, P = 0.36) or with disease progression in Balb/c IL1ra-/- mice at 22 to 23 weeks of age (Figure 6c, n = 5, P = 0.54) or 31 to 32 weeks of age (Figure 6c, n = 3, P = 0.19) compared to age-matched wild type controls. However, as IL1ra-/- mice showed a decreased number of osteoclasts before disease onset, this suggests a change in the activation profile of osteoclasts with disease establishment. Activated osteoclasts are no longer decreased in number compared to wild type mice and, if anything, a trend to increase is seen. Similarly the increase in bone mass seen before disease onset is also lost with disease establishment. This, together with a block in differentiation of the mesenchymal progenitors with osteogenic potential to the osteoblast lineage, suggests an overall accelerated bone loss in Balb/c IL1 ra-/- with disease onset and progression.
The role of the bone marrow niche and mesenchymal stem cell in haemopoiesis and regulation of inflammation is becoming progressively recognised [14–16]. Despite the fact that in RA there are clearly defined disturbances in the haemopoietic and immune system, changes in bone marrow mesenchymal stem cells and their progeny, which may drive those modifications, have not been studied. To address this question we have used the IL1ra-/- on a Balb/c background. This model has histopathological features, which closely resemble arthritis present in patients affected by RA with synovitis, inflammatory cellular infiltration, which includes lymphocytes, pannus formation and periarticular bone erosions. The knocking out of the interleukin-1 receptor antagonist is permissive but not solely responsible for the occurrence of RA-like arthropathy as the occurrence depends also on the mouse strain. Moreover, the histopathological features of the disease differs from those described in patients who harbour a deletion of the interleukin-1 receptor antagonist gene recently described . In those patients there is multiple chronic osteomyelitis, and bone erosions are intraosseous and not periarticular as seen in our murine model or in patients affected by RA. Therefore, the Balb/c IL1ra-/- is a valuable model to study events which occur over time and in the BM. Obtaining BM samples from patients affected by RA and who have not undergone treatment is difficult.
Here, for the first time, we provide evidence of changes in the composition of the bone marrow niche present already before the development of RA-like disease. We have shown a deficiency in mesenchymal progenitors with adipogenic potential and bone marrow adiposity together with a decrease in the maturation of osteoclasts before disease development. Moreover, this was present only in Balb/c IL1 ra-/- mice, who progressed to develop RA-like disease and not in C57BL6 IL1ra-/-, which have been shown not to develop RA-like arthritis, suggesting an association of these abnormalities with RA development. Although it is difficult to predict the precise cascade of events leading from low adipogenesis to decreased activation of osteoclasts, there is evidence that the two processes may be linked. Mature adipocytes release adipokines such as leptin, ghrelin and adiponectin, or growth factors such as monocytes chemotactic protein 1 (MCP-1) . For examples, MCP-1 has been shown to mediate osteoclastogenesis and bone resorption . Further studies are now needed to understand the genetic alterations and the cascade of events leading to those abnormalities.
Regardless of the precise cascade of events, our data are in agreement with other published data. In the study by Naivares et al (2009) low bone marrow adiposity has been positively correlated with the ability to support proliferation of hematopoietic progenitors . Lack of adipogenesis in AZIP/F1 recipient mice (genetically incapable of forming adipocytes) enhanced hematopoietic recovery after lethal irradiation by enhancing engraftment of short term progenitors . Adipocyte-rich marrow was shown to harbour a decreased frequency of progenitors and relatively quiescent stem cells . Therefore the reduction in adipogenesis in Balb/c IL1ra-/- mice supports the notion of an enhanced stimulation of the HSC to proliferate and is in agreement with the study by Schonland et al. (2003) where individuals with the HLA-DRB104 haplotype, shown to be more at risk for developing rheumatoid arthritis, had accelerated telomere shortening of both lymphocytes and neutrophils, a marker of cellular proliferation and ageing of haemopoietic progenitors .
Dysregulated adipogenesis may be responsible for the establishment of a proinflammatory environment. Adiponectin has been suggested to have a role in vivo for immediate moderation of inflammatory reactions occurring after invasion by foreign pathogens and prevents an excessive and prolonged inflammatory response. Indeed lipopolysaccharide (LPS) induced expression of TNFα mRNA in macrophages and was markedly suppressed by pre-treatment with recombinant adiponectin . Adiponectin pre-treated macrophages failed to release TNF-α in response to LPS . Therefore it is not unreasonable to suggest that the low number of adipocytes found in the bone marrow of Balb/c IL1ra-/- mice may lead to reduced levels of adipokines, such as adiponectin, which in turn reduce activation of macrophages and allows increased presence of inflammatory cytokines such as TNF-α, following the start of any inflammatory process. Indeed, elevated levels of TNFRII, a surrogate soluble receptor, which parallel levels of TNF-α, has been found elevated in the preclinical phase of disease of patients that go on to develop RA up to eight years after .
MSC share many properties with fibroblast-like synoviocytes (FLS) , the cells responsible for the thickening of the synovium in the joint in RA and perpetuation of the inflammatory process by recruiting and supporting the survival of inflammatory cells . It is thought that MSC may even contribute to the FLS pool in the joint. When the bone marrow of green fluorescence protein (GFP) transgenic donor mice was transplanted into lethally irradiated recipient mice, it was shown that normal FLS contained a minor fraction (1.2%) of GFP+ cells . As FLS undergo increased proliferation it is not unreasonable to suggest that MSC may undergo expansion in the bone marrow too at disease onset and change the composition of the bone marrow niche. Our data point to increased numbers of MSC following establishment of the disease. Our findings are not in agreement with a previous study measuring the number of bone marrow mesenchymal progenitors in patients affected by RA, where no significant difference was found . The reason for the apparent discrepancy may lie in the fact that most patients included in the study by Kastrinaki et al. (2008)  had undergone treatment and those who had not undergone treatment were a very small number with a wide age range. This may have compromised the detection of any difference, especially considering that the number of CFU-F tend to decrease with age .
Of interest is the accumulation of progenitors, which are unable to differentiate to the osteoblast lineage. The mechanism leading to MSC accumulation and blocking of their differentiation are unclear and likely due to a complex interplay of cytokines and cellular cross talks, mostly related to the in vivo inflammatory environment. When these cells were induced to differentiate to the osteoblast lineage in vitro they showed formation of colony forming unit-osteoblasts, which were alkaline phosphatase positive and did not differ in the pattern of staining from those derived from the bone marrow of their wild type age-matched controls. Proinflammatory cytokines such as TNF-α and IL1β have been shown to block osteogenic differentiation in vitro [26, 27] and support our findings. The accumulation of MSC, known to secrete RANKL, may also lend an explanation to the loss of defective osteoclastogenesis observed in the Balb/c IL1ra-/- animals before disease onset. Indeed, our data shows that with the establishment of disease the number of osteoclasts is no longer significantly decreased and, if anything, it exhibits a trend to increase. This is in agreement with the well-known increase in the number of activated osteoclasts reported in the joints of patients with RA and with data suggesting that at very early stages of inflammation, when levels of TNF-α are low, mesenchymal stem cells are required for osteoclastogenesis . All together our data are in agreement with reports of RA patients developing systemic osteoporosis with time  and of systemic accelerated bone loss in another model of inflammatory arthritis mainly as the result of arrested osteoblast function . Ways to induce effective differentiation of the mesenchymal progenitors to the osteoblast lineage may provide both a way to reduce expansion of MSC and prevent systemic bone loss.
The accumulation of MSC raises the intriguing question whether these cells, known for their immunosuppressive properties, are exerting the expected anti-inflammatory action and whether the proposed administration of additional MSC, as novel therapeutic strategy in RA, would have the desired effect of dampening the auto-immune responses. Despite a wealth of literature describing the immunosuppressive ability of MSC, more recently a pro-inflammatory phenotype of MSC has also been described [31, 32]. This requires activation of TLR4 and possibly TLR3 receptors present on MSC. Indeed overexpression of TLR3 and TLR4 has been described in synovial fibroblasts of patients affected by RA and beg the question whether bone marrow mesenchymal stem cells in RA patients show similar overexpression and have a pro-inflammatory phenotype as a result of their engagement . The fact that administration of murine MSC in models of RA disease has given contrasting results [34, 35] highlights that this is a potential problem and calls for a closer analysis of the inflammatory phenotype of the patients' MSC at the time of active disease, following expansion before administration and after administration to the patient. This may help to determine whether MSC preparation varies in terms of predisposition to acquire a pro-inflammatory phenotype or whether this is an acquired characteristic as a result of contact with the patients' cellular environment. Moreover, it may establish whether the cellular environment confers the pro-inflammatory phenotype depending on the disease stage and status of remission.
We have shown an accumulation of MSC progenitors with the onset of RA-like disease and a block in their differentiation to osteoblasts. These data highlight the need for therapeutic intervention with molecules capable of inducing differentiation of MSC to osteoblasts to prevent the onset of osteoporosis. Moreover, it puts into question whether additional administration of MSC proposed as treatment to reduce the autoimmune response  is required and would be efficacious. More studies into the molecular mechanism leading to enhanced maintenance of MSC in RA-like disease, their pro-inflammatory phenotype and ways to interferes with this are required. Small molecules such as glycogen synthase kinase -3 inhibitors have been shown to have anti-inflammatory properties and to drive commitment of MSC to osteogenic lineage [36, 37], suggesting they may have a therapeutic impact in both reducing inflammation and bone loss.
- Balb/c IL1ra-/-:
Interleukin-1 receptor antagonist knock out mouse on a Balb/c background
bone marrow cells
Colony Forming Unit-Adipocyte
Colony Forming Unit-Fibroblasts
Colony Forming Unit-Osteoblast
Dulbecco's modified Eagle medium
fetal calf serum
green fluorescence protein
haemopoietic stem cell
monocytes chemotactic protein 1
mesenchymal stem cells
tartrate resistant acid phosphatise
wild type mice.
We are very grateful to Orla Gallagher, Darren Lath, Julia Hough and Holly Evans for expert technical assistance. STM was funded by BBSRC, LK was funded by LRF and AG was funded by AstraZeneca. This study was funded by the University of Sheffield.
- Marinova-Mutafchieva L, Williams RO, Funa K, Maini RN, Zvaifler NJ: Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis. Arthritis Rheum. 2002, 46: 507-513. 10.1002/art.10126.View ArticlePubMedGoogle Scholar
- Papadaki HA, Kritikos HD, Gemetzi C, Koutala H, Marsh JC, Boumpas DT, Eliopoulos GD: Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect. Blood. 2002, 99: 1610-1619. 10.1182/blood.V99.5.1610.View ArticlePubMedGoogle Scholar
- Snowden JA, Passweg J, Moore JJ, Milliken S, Cannell P, Van Laar J, Verburg R, Szer J, Taylor K, Joske D, Rule S, Bingham SJ, Emery P, Burt RK, Lowenthal RM, Durez P, McKendry RJ, Pavletic SZ, Espigado I, Jantunen E, Kashyap A, Rabusin M, Brooks P, Bredeson C, Tyndall A: Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from the EBMT and ABMTR. J Rheumatol. 2004, 31: 482-488.PubMedGoogle Scholar
- Schonland SO, Lopez C, Widmann T, Zimmer J, Bryl E, Goronzy JJ, Weyand CM: Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci USA. 2003, 100: 13471-13476. 10.1073/pnas.2233561100.PubMed CentralView ArticlePubMedGoogle Scholar
- Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT: Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003, 425: 841-846. 10.1038/nature02040.View ArticlePubMedGoogle Scholar
- Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L: Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003, 425: 836-841. 10.1038/nature02041.View ArticlePubMedGoogle Scholar
- Purton LE, Scadden DT: Osteoclasts eat stem cells out of house and home. Nat Med. 2006, 12: 610-611. 10.1038/nm0606-610.View ArticlePubMedGoogle Scholar
- Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ: Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009, 460: 259-263. 10.1038/nature08099.PubMed CentralView ArticlePubMedGoogle Scholar
- De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001, 44: 1928-1942. 10.1002/1529-0131(200108)44:8<1928::AID-ART331>3.0.CO;2-P.View ArticlePubMedGoogle Scholar
- Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y: Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med. 2000, 191: 313-320. 10.1084/jem.191.2.313.PubMed CentralView ArticlePubMedGoogle Scholar
- Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP: Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. 2001, 7: 563-568. 10.1038/87887.View ArticlePubMedGoogle Scholar
- Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I: Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells. 2004, 22: 675-682. 10.1634/stemcells.22-5-675.View ArticlePubMedGoogle Scholar
- Wu X, Peters JM, Gonzalez FJ, Prasad HS, Rohrer MD, Gimble JM: Frequency of stromal lineage colony forming units in bone marrow of peroxisome proliferator-activated receptor-alpha-null mice. Bone. 2000, 26: 21-26. 10.1016/S8756-3282(99)00238-0.View ArticlePubMedGoogle Scholar
- Tyndall A, Uccelli A: Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks. Bone Marrow Transplant. 2009, 43: 821-828. 10.1038/bmt.2009.63.View ArticlePubMedGoogle Scholar
- Fibbe WE, Nauta AJ, Roelofs H: Modulation of immune responses by mesenchymal stem cells. Ann N Y Acad Sci. 2007, 1106: 272-278. 10.1196/annals.1392.025.View ArticlePubMedGoogle Scholar
- Dazzi F, Ramasamy R, Glennie S, Jones SP, Roberts I: The role of mesenchymal stem cells in haemopoiesis. Blood Rev. 2006, 20: 161-171. 10.1016/j.blre.2005.11.002.View ArticlePubMedGoogle Scholar
- Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, Hessner MJ, Verbsky J: An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009, 360: 2438-2444. 10.1056/NEJMoa0809568.PubMed CentralView ArticlePubMedGoogle Scholar
- Gimble JM, Robinson CE, Wu X, Kelly KA: The function of adipocytes in the bone marrow stroma: an update. Bone. 1996, 19: 421-428. 10.1016/S8756-3282(96)00258-X.View ArticlePubMedGoogle Scholar
- Lu Y, Cai Z, Xiao G, Keller ET, Mizokami A, Yao Z, Roodman GD, Zhang J: Monocyte chemotactic protein-1 mediates prostate cancer-induced bone resorption. Cancer Res. 2007, 67: 3646-3653. 10.1158/0008-5472.CAN-06-1210.View ArticlePubMedGoogle Scholar
- Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y: Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000, 96: 1723-1732.PubMedGoogle Scholar
- Karlson EW, Chibnik LB, Tworoger SS, Lee IM, Buring JE, Shadick NA, Manson JE, Costenbader KH: Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum. 2009, 60: 641-652. 10.1002/art.24350.PubMed CentralView ArticlePubMedGoogle Scholar
- Jones EA, English A, Henshaw K, Kinsey SE, Markham AF, Emery P, McGonagle D: Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum. 2004, 50: 817-827. 10.1002/art.20203.View ArticlePubMedGoogle Scholar
- Mor A, Abramson SB, Pillinger MH: The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol. 2005, 115: 118-128. 10.1016/j.clim.2004.12.009.View ArticlePubMedGoogle Scholar
- Li X, Makarov SS: An essential role of NF-κB in the "tumor-like" phenotype of arthritic synoviocytes. Proc Natl Acad Sci U S A. 2006, 103: 17432-17437. 10.1073/pnas.0607939103.PubMed CentralView ArticlePubMedGoogle Scholar
- Kastrinaki MC, Sidiropoulos P, Roche S, Ringe J, Lehmann S, Kritikos H, Vlahava VM, Delorme B, Eliopoulos GD, Jorgensen C, Charbord P, Haupl T, Boumpas DT, Papadaki HA: Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis. 2008, 67: 741-749. 10.1136/ard.2007.076174.View ArticlePubMedGoogle Scholar
- Lacey DC, Simmons PJ, Graves SE, Hamilton JA: Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation. Osteoarthritis Cartilage. 2009, 17: 735-742. 10.1016/j.joca.2008.11.011.View ArticlePubMedGoogle Scholar
- Lange J, Sapozhnikova A, Lu C, Hu D, Li X, Miclau T, Marcucio RS: Action of IL-1beta during fracture healing. J Orthop Res. 28: 778-784.
- Kitaura H, Sands MS, Aya K, Zhou P, Hirayama T, Uthgenannt B, Wei S, Takeshita S, Novack DV, Silva MJ, Abu-Amer Y, Ross FP, Teitelbaum SL: Marrow stromal cells and osteoclast precursors differentially contribute to TNF-alpha-induced osteoclastogenesis in vivo. J Immunol. 2004, 173: 4838-4846.View ArticlePubMedGoogle Scholar
- Solomon DH, Finkelstein JS, Shadick N, LeBoff MS, Winalski CS, Stedman M, Glass R, Brookhart MA, Weinblatt ME, Gravallese EM: The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis Rheum. 2009, 60: 1624-1631. 10.1002/art.24551.PubMed CentralView ArticlePubMedGoogle Scholar
- Ma YD, Park C, Zhao H, Oduro KA, Tu X, Long F, Allen PM, Teitelbaum SL, Choi K: Defects in osteoblast function but no changes in long-term repopulating potential of hematopoietic stem cells in a mouse chronic inflammatory arthritis model. Blood. 2009, 114: 4402-4410. 10.1182/blood-2008-12-196311.PubMed CentralView ArticlePubMedGoogle Scholar
- Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM: A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One. 5: e10088-10.1371/journal.pone.0010088.
- Romieu-Mourez R, Francois M, Boivin MN, Bouchentouf M, Spaner DE, Galipeau J: Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol. 2009, 182: 7963-7973. 10.4049/jimmunol.0803864.View ArticlePubMedGoogle Scholar
- Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, Gay RE, Gay S, Kyburz D: Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 2008, 58: 3684-3692. 10.1002/art.24140.View ArticlePubMedGoogle Scholar
- Schurgers E, Kelchtermans H, Mitera T, Geboes L, Matthys P: Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Research & Therapy. 12: R31-10.1186/ar2939.
- Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G: Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007, 56: 1175-1186. 10.1002/art.22511.View ArticlePubMedGoogle Scholar
- Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, Woodgett JR, Ivashkiv LB: IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity. 2006, 24: 563-574. 10.1016/j.immuni.2006.02.014.View ArticlePubMedGoogle Scholar
- Kulkarni NH, Onyia JE, Zeng Q, Tian X, Liu M, Halladay DL, Frolik CA, Engler T, Wei T, Kriauciunas A, Martin TJ, Sato M, Bryant HU, Ma YL: Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J Bone Miner Res. 2006, 21: 910-920. 10.1359/jbmr.060316.View ArticlePubMedGoogle Scholar
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