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Inhibition of TAK1 and/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions
Tissue Eng Part A. 2014 Feb 18;
Authors: van Beuningen HM, de Vries-van Melle ML, Vitters EL, Schreurs W, van den Berg WB, van Osch G, van der Kraan PM
ABSTRACT Objective: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases. Methods: hMSCs were cultured in pellets. During early chondrogenic differentiation these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the JAK-inhibitor tofacitinib and/or the TAK1-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor and results of these studies were confirmed with hMSCs from adult donors. Results: Exposure to OAS-CM resulted in pellets with a much lower GAG content, reflecting inhibited chondrogenic differentiation. This was accompanied by decreased mRNA levels of aggrecan, type II collagen and Sox9, and increased levels of MMP1, MMP3, MMP13, ADAMTS4 and ADAMTS5. Both tofacitinib (JAK-inhibitor) and oxozeaenol (TAK1 inhibitor) significantly increased the GAG content of the pellets in osteoarthritis(OA)-like conditions. The combination of both protein kinase inhibitors showed an additive effect on GAG content. In agreement with this, in the presence of OAS-CM both tofacitinib and oxozeaenol increased mRNA expression of sox9. Expression of aggrecan and type II collagen was also up-regulated, but this only reached significance for aggrecan after TAK1 inhibition. Both inhibitors decreased the mRNA levels of MMP1, 3 and 13 in the presence of OAS-CM. Moreover, oxozeaenol also significantly down-regulated the mRNA levels of aggrecanases ADAMTS4 and ADAMTS5. When combined, the inhibitors caused additive reduction of OA-induced MMP1 mRNA expression. Counteraction of OAS-CM-induced inhibition of chondrogenesis by these protein kinase inhibitors was confirmed with hMSCs of two different adult donors. Both tofacitinib and oxozeaenol significantly improved GAG content in cell pellets from these adult donors. Conclusions: Tofacitinib and oxozeaenol partially prevent the inhibition of chondrogenesis by factors secreted by OA synovium. Their effects are additive. This indicates that these protein kinase inhibitors can potentially be used to improve cartilage formation under the conditions occurring in osteoathritic, or otherwise inflamed, joints.
PMID: 24547725 [PubMed – as supplied by publisher]
Mesenchymal stem cells: uses in osteoarthritis
Joint Bone Spine. 2013 Dec;80(6):565-7
Authors: Jorgensen C
PMID: 24060400 [PubMed – in process]
Mesenchymal stem cells for cartilage repair in osteoarthritis
Stem Cell Res Ther. 2012 Jul 9;3(4):25
Authors: Gupta PK, Das AK, Chullikana A, Majumdar AS
ABSTRACT: Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived ‘mesenchymal stem cells’ or ‘mesenchymal stromal cells’, with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.
PMID: 22776206 [PubMed – as supplied by publisher]
Differential responsiveness to 17β-estradiol of mesenchymal stem cells from postmenopausal women between osteoporosis and osteoarthritis
Osteoporos Int. 2012 Oct;23(10):2469-78
Authors: Jin WJ, Jiang SD, Jiang LS, Dai LY
UNLABELLED: Differential osteogenic potential and responsiveness to 17β-estradiol (E2) of mesenchymal stem cells (MSCs) were found between postmenopausal women with osteoporosis (OP) and osteoarthritis (OA). These results suggest differential biological mechanisms of estrogen deficiency in regulation of bone remodeling between OP and OA.
INTRODUCTION: OP and OA are two common disorders in postmenopausal women. The inverse relationship has been suggested between OP and OA, but their mechanisms that relate to estrogen deficiency are not fully understood. The aim of this study was to compare the differential responsiveness to E2 of MSCs from osteoporotic versus osteoarthritic donors.
METHODS: Twenty postmenopausal patients, ten with osteoporotic hip fractures and ten with hip osteoarthritis, were included into this study. MSCs were derived from cancellous bones of femoral heads from OA and OP donors and cultured in osteogenic and adipogenic medium with or without E2 added. The alkaline phosphatase (ALP) activity, calcium content, calcified nodules, lipid droplets, messenger RNA (mRNA) expression of ALP, osteocalcin (OC), collagen 1α (COL1α), peroxisome proliferators-activated receptor γ2 (PPARγ2) and lipoprotein lipase (LPL) were measured and compared between two groups with OP and OA.
RESULTS: In osteogenic medium, ALP activity, calcium content and mRNA expression of OC and COL1α in MSCs from OA were significantly higher than those from OP group. In adipogenic condition, there was no significant difference in lipid droplets formation and mRNA expression of PPARγ2 and LPL between OP and OA groups. With E2 added in osteogenic medium, ALP activity, calcium content and OC mRNA were significantly higher in OP group than in OA group, whereas E2 had no significant effect on lipid droplet formation and mRNA expression of PPARγ2 and LPL.
CONCLUSION: Differential osteogenic potential and responsiveness to E2 of MSCs were found between postmenopausal women with OP and OA. These results may provide information for clinical application of MSCs in the differential setting of estrogen deficiency.
PMID: 22159632 [PubMed – indexed for MEDLINE]
Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells
Tissue Eng Part A. 2012 Jan;18(1-2):45-54
Authors: Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, van der Kraan PM
Articular cartilage has a very limited intrinsic repair capacity leading to progressive joint damage. Therapies involving tissue engineering depend on chondrogenic differentiation of progenitor cells. This chondrogenic differentiation will have to survive in a diseased joint. We postulate that catabolic factors in this environment inhibit chondrogenesis of progenitor cells. We investigated the effect of a catabolic environment on chondrogenesis in pellet cultures of human mesenchymal stem cells (hMSCs). We exposed chondrogenically differentiated hMSC pellets, to interleukin (IL)-1α, tumor necrosis factor (TNF)-α or conditioned medium derived from osteoarthritic synovium (CM-OAS). IL-1α and TNF-α in CM-OAS were blocked with IL-1Ra or Enbrel, respectively. Chondrogenesis was determined by chondrogenic markers collagen type II, aggrecan, and the hypertrophy marker collagen type X on mRNA. Proteoglycan deposition was analyzed by safranin o staining on histology. IL-1α and TNF-α dose-dependently inhibited chondrogenesis when added at onset or during progression of differentiation, IL-1α being more potent than TNF-α. CM-OAS inhibited chondrogenesis on mRNA and protein level but varied in extent between patients. Inhibition of IL-1α partially overcame the inhibitory effect of the CM-OAS on chondrogenesis whereas the TNF-α contribution was negligible. We show that hMSC chondrogenesis is blocked by either IL-1α or TNF-α alone, but that there are additional factors present in CM-OAS that contribute to inhibition of chondrogenesis, demonstrating that catabolic factors present in OA joints inhibit chondrogenesis, thereby impairing successful tissue engineering.
PMID: 21770865 [PubMed – indexed for MEDLINE]
Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level
Arthritis Rheum. 2008 Jun;58(6):1731-40
Authors: Jones EA, Crawford A, English A, Henshaw K, Mundy J, Corscadden D, Chapman T, Emery P, Hatton P, McGonagle D
OBJECTIVE: Arthritic synovial fluid (SF) contains mesenchymal stem cells (MSCs), which could simply reflect their shedding from diseased joint structures. This study used the bovine model to explore SF MSCs in health and enumerated them at the earliest stages of human osteoarthritis (OA) in radiographically normal joints.
METHODS: Clonogenicity and multipotentiality of normal bovine SF MSCs were compared with donor-matched bone marrow (BM) MSCs at the single-cell level. The colony-forming unit-fibroblastic assay was used for MSC enumeration. The XTT assay was employed to assess cell proliferation, and flow cytometry was used to investigate the marker phenotype of bovine and human SF MSCs.
RESULTS: Single MSCs were present in normal bovine SF, and 96% of them were able to expand at least 1 million-fold. These cells were CD271-, multipotential, considerably more clonogenic, and less adipogenic than matched BM MSCs. In both pellet assays and on polyglycolic acid scaffolds, SF clones displayed consistent chondrogenic differentiation, while BM clones were variable. MSCs were present in arthroscopically normal human joints and were increased 7-fold in early OA (P = 0.034). Their numbers correlated with numbers of free microscopic synovial tissue fragments (r = 0.826, P < 0.0001). OA SF had a growth-promoting effect on synovial MSCs.
CONCLUSION: This study confirms the presence of MSCs in normal SF and shows their numerical increase in early human OA. SF MSCs are likely to originate from synovium. These findings provide a platform for the exploration of the potential role of SF MSCs in joint homeostasis and for investigation of their utility in novel joint regeneration strategies.
PMID: 18512779 [PubMed - indexed for MEDLINE]
Differential proteome of bone marrow mesenchymal stem cells from osteoarthritis patients
Osteoarthritis Cartilage. 2008 Aug;16(8):929-35
Authors: Rollín R, Marco F, Camafeita E, Calvo E, López-Durán L, Jover JA, López JA, Fernández-Gutiérrez B
OBJECTIVE: Adult mesenchymal stem cells (MSCs) are multipotent cells whose primary reservoir is bone marrow (BM). Following situations of extensive tissue damage, MSCs are mobilized and migrate to the site of injury. Osteoarthritis (OA) is a condition that involves extensive cartilage and bone damage. To gain insight into the pathogenesis of OA, we have analyzed the differential BM-MSCs proteome of OA patients.
METHODS: MSCs protein extracts were prepared from BM aspirates from six patients with OA and from six hip fracture subjects without OA, and analyzed by Two-dimensional gels, using the differential in-gel electrophoresis approach. Differentially expressed proteins were identified by mass spectrometry. In addition, the chemotactic responses of OA and control MSCs were assessed.
RESULTS: The majority of proteins that changed at least 1.5-fold (P<0.05) belonged to the following three categories: metabolic enzymes (14 proteins, 36%), cytoskeleton/motility (12 proteins, 32%), and transporters (three proteins, 8%). In OA MSCs, a high percentage of metabolic enzymes (n=8, 57%) were up-regulated and most of the proteins related to cytoskeleton/motility (n=9, 75%) were down-regulated. There was a significant increase in the migration response of OA MSCs to platelet-derived growth factor-BB (chemotaxis index CI: 5.13+/-1.19 vs 3.35+/-0.42, P=0.043).
CONCLUSIONS: In this study, we have described the differential proteome of BM-MSCs from OA patients together with an increased chemotactic response of these cells in the context of OA. These results could indicate an activation of OA BM-MSCs in response to chemotactic signals sent by the altered subchondral bone in an attempt to heal damaged tissue.
PMID: 18222713 [PubMed - indexed for MEDLINE]
Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.
Stem Cells. 2007 Dec;25(12):3244-51
Authors: Scharstuhl A, Schewe B, Benz K, Gaissmaier C, Bühring HJ, Stoop R
Osteoarthritis (OA) is a multifactorial disease strongly correlated with history of joint trauma, joint dysplasia, and advanced age. Mesenchymal stem cells (MSCs) are promising cells for biological cartilage regeneration. Conflicting data have been published concerning the availability of MSCs from the iliac crest, depending on age and overall physical fitness. Here, we analyzed whether the availability and chondrogenic differentiation capacity of MSCs isolated from the femoral shaft as an alternative source is age- or OA etiology-dependent. MSCs were isolated from the bone marrow (BM) of 98 patients, categorized into three OA-etiology groups (age-related, joint trauma, joint dysplasia) at the time of total hip replacement. All BM samples were characterized for cell yield, proliferation capacity, and phenotype. Chondrogenic differentiation was studied using micromass culture and analyzed by histology, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction. Significant volumes of viable BM (up to 25 ml) could be harvested from the femoral shaft without observing donor-site morbidity, typically containing >10(7) mononuclear cells per milliliter. No correlation of age or OA etiology with the number of mononuclear cells in BM, MSC yield, or cell size was found. Proliferative capacity and cellular spectrum of the harvested cells were independent of age and cause of OA. From all tested donors, MSCs could be differentiated into the chondrogenic lineage. We conclude that, irrespective of age and OA etiology, sufficient numbers of MSCs can be isolated and that these cells possess an adequate chondrogenic differentiation potential. Therefore, a therapeutic application of MSCs for cartilage regeneration of OA lesions seems feasible. Disclosure of potential conflicts of interest is found at the end of this article.
PMID: 17872501 [PubMed – indexed for MEDLINE]
Mesenchymal stem cells in osteoarthritis
Curr Opin Rheumatol. 2004 Sep;16(5):599-603
Authors: Luyten FP
PURPOSE OF REVIEW: Accumulating evidence indicates that every tissue contains stem cells. Our understanding of the biology of stem cells reveals that these cell populations have a critical role in the homeostasis and repair of tissues. Besides the local stem cell niches, additional compartments in the body such as the bone marrow may serve as reservoirs for stem cell populations. On more extensive tissue damage, and guided by local repair responses, “reparative” cell populations are mobilized from more distant stem cell reservoirs and migrate to the site of injury, thereby contributing in many aspects of local tissue repair.
RECENT FINDINGS: Osteoarthritis has long been regarded as an imbalance between destructive and reparative processes. The lack of repair of the weight-bearing articular cartilage and the associated subchondral bone changes are considered of critical importance in the progression of the disease. Recent findings indicate a depletion and/or functional alteration of mesenchymal stem cell populations in osteoarthritis. These preliminary data suggest that in joint diseases such as osteoarthritis, it is of importance to investigate further the involvement of the stem cell pool in the mechanisms contributing to joint homeostasis and driving disease progression.
SUMMARY: In view of the emerging body of evidence pointing to a potential therapeutic utility of stem cell technology, it is not surprising that local delivery of mesenchymal stem cells has been explored as a therapeutic approach in animal models of osteoarthritis.
PMID: 15314501 [PubMed – indexed for MEDLINE]
Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis
Arthritis Rheum. 2002 Mar;46(3):704-13
Authors: Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F
OBJECTIVE: Mesenchymal stem cells (MSCs) are resident in the bone marrow throughout normal adult life and have the capacity to differentiate along a number of connective tissue pathways, among them bone, cartilage, and fat. To determine whether functionally normal MSC populations may be isolated from patients with advanced osteoarthritis (OA), we have compared cells from patients undergoing joint replacement with cells from normal donors. Cell populations were compared in terms of yield, proliferation, and capacity to differentiate.
METHODS: MSCs were prepared from bone marrow aspirates obtained from the iliac crest or from the tibia/femur during joint surgery. In vitro chondrogenic activity was measured as glycosaminoglycan and type II collagen deposition in pellet cultures. Adipogenic activity was measured as the accumulation of Nile Red O-positive lipid vacuoles, and osteogenic activity was measured as calcium deposition and by von Kossa staining.
RESULTS: Patient-derived MSCs formed colonies in primary culture that were characteristically spindle-shaped with normal morphology. The primary cell yield in 36 of 38 cell cultures from OA donors fell within the range found in cultures from normal donors. However, the proliferative capacity of patient-derived MSCs was significantly reduced. There was a significant reduction in in vitro chondrogenic and adipogenic activity in cultures of patient-derived cells compared with that in normal cultures. There was no significant difference in in vitro osteogenic activity. There was no decline in chondrogenic potential with age in cells obtained from individuals with no evidence of OA.
CONCLUSION: These results raise the possibility that the increase in bone density and loss of cartilage that are characteristic of OA may result from changes in the differentiation profile of the progenitor cells that contribute to the homeostatic maintenance of these tissues.
PMID: 11920406 [PubMed – indexed for MEDLINE]