Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis

Chan, B.Y.; Fuller, Emily; Russell, Amy K.; Smith, Susan; Smith, Margaret M.; Jackson, M.T.; Cake, Martin; Read, Roger W.; Bateman, John F.; Sambrook, Philip N.; Little, Christopher B.

doi:10.1016/j.joca.2011.04.014

Cited by 174 publications

(187 citation statements)

References 48 publications

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“…Therefore, the functional changes of chondrocytes play an important role by contributing to the degradation of the articular cartilage and thus to the pathogenesis of OA (15,16). Several studies have reported that there is a very low proliferative activity in osteoarthritic chondrocytes, which might be an efficient treatment to cure or even delay the progression of OA by promoting chondrocyte proliferation (17,18).…”

Section: Discussionmentioning

confidence: 99%

Millimeter wave treatment promotes chondrocyte proliferation via G1/S cell cycle transition

et al. 2012

Int J Mol Med

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Abstract. Millimeter waves, high-frequency electromagnetic waves, can effectively alleviate the clinical symptoms in osteoarthritis patients, as a non-pharmaceutical and non-invasive physical therapy regimen. However, the molecular mechanisms of the therapeutic effects of millimeter wave treatment are not well understood. In the present study, the effect of millimeter waves on the G 1 /S cell cycle progression in chondrocytes and the underlying mecha nism was investigated. Chondrocytes isolated from the knee of SD rats were cultured and identified using toluidine blue staining. The second generation chondrocytes were collected and stimulated with or without millimeter waves for 48 h. Chondrocyte viability was analyzed using the MTT assay. The cell cycle distribution of chondrocytes was analyzed by flow cytometry. mRNA and protein expression levels of cyclin D1, cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) and p21 were detected using real-time PCR and western blotting, respectively. Millimeter wave stimulation was found to significantly enhance chondrocyte viability. Moreover, the percentage of chondrocytes in the G 0 /G 1 phase was significantly decreased, whereas that in the S phase was significantly increased. In addition, following millimeter wave treatment, cyclin D1, CDK4 and CDK6 expression was significantly upregulated, whereas p21 expression was significantly downregulated. The results indicate that millimeter wave treatment promotes chondrocyte proliferation via cell cycle progression. IntroductionOsteoarthritis (OA), the most frequent arthropathy, is characterized by progressive degradation of hyaline articular cartilage and is associated with aging (1). A complex interplay of mechanical, and functional changes of chondrocytes could precipitate the imbalance between matrix anabolic and catabolic processes in articular cartilage and thus the pathogenesis of OA (2,3). Chondroctyes can rapidly respond to changes in the articular microenvironment and regulate the dynamic equilibrium between the anabolism and catabolism of the extracellular matrix (ECM), which plays a crucial role in the maintenance of the cartilage function (4). Therefore, enhancing chondrocyte function might be an efficient treatment to cure or even delay the progression of OA by promoting chondrocyte proliferation.The cell cycle plays an important role in the influence on chondrocyte function, which takes place in chondrocytes leading to its division and duplication. Cell cycle control is a highly regulated process that involves a complex cascade of events, in which regulation can be realized through a complicated network by cyclins, cyclin-dependent kinases (CDKs) and cyclin dependent kinase inhibitors (CDKI). G 1 /S transition, one of the two main checkpoints, is a rate-limiting step in the cell cycle and regulates cell proliferation (5,6). Cyclin D1 is a key cell cycle regulatory protein, which binds to CDK4 or CDK6 to control cell cycle progression from the G 1 to the S phase (7). Meanwhile, p21 competes with cyclin D1 for bindin...

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Section: Discussionmentioning

confidence: 99%

Millimeter wave treatment promotes chondrocyte proliferation via G1/S cell cycle transition

et al. 2012

Int J Mol Med

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“…A site in question is the subchondral plate in the joints, which has been highlighted by a series of studies indicating that loss of the Wnt inhibitors is a key player in the development of osteoarthritis (178,179); however, whether this will occur with the therapeutic strategies and thereby become a potential serious side effect remains to be elucidated. In addition, nerve compression is frequently observed in osteopetrotic/osteosclerotic phenotypes (14,18,24), and in the case of the mutations related to the Wnt/LRP5 system, this is a consequence of the high bone volume.…”

Section: The Wnt/lrp5 Systemmentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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“…This indicates a negative feedback loop wherein Wnt/β-catenin signaling in human chondrocytes played an anti-catabolic role by preventing MMP expression induced by IL-1β [88]. Another investigation also found that SOST, a potent inhibitor of canonic Wnt signaling that binds to Wnt receptor Low-density-lipoprotein receptor-related protein 5/6 (LRP5/6), inhibited further degradation of OA cartilage [89]. More recently, bone morphogenetic protein 2 (BMP-2) signaling was found to increase β-catenin nuclear translocation, LRP-5 expression, MMP levels (MMP-9, MMP-13, and MMP 14), ADAMTS-5, and collagen X expression.…”

Section: Potential Mechanisms Involved In Oa Progression and Msc Treamentioning

confidence: 92%

Treatment of osteoarthritis with mesenchymal stem cells

Wang

Cao

2014

Sci. China Life Sci.

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Osteoarthritis (OA) is one of the most prevalent joint diseases with prominent symptoms affecting the daily life of millions of middle aged and elderly people. Despite this, there are no successful medical interventions that can prevent the progressive destruction of OA joints. The onset of pathological changes in OA is associated with deviant activity of mesenchymal stem cells (MSCs), the multipotent precursors of connective tissue cells that reside in joints. Current therapies for OA have resulted in poor clinical outcomes without repairing the damaged cartilage. Intra-articular delivery of culture-expanded MSCs has opened new avenues of OA treatment. Pre-clinical and clinical trials demonstrated the feasibility, safety, and efficacy of MSC therapy. The Wnt/β-catenin, bone morphogenetic protein 2, Indian hedgehog, and Mitogen-activated protein kinase signaling pathways have been demonstrated to be involved in OA and the mechanism of action of MSC therapies. osteoarthritis, mesenchymal stem cells, intra-articular delivery Citation:Wang W, Cao W. Treatment of osteoarthritis with mesenchymal stem cells.

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Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis

Abstract: These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.

Cited by 174 publications

References 48 publications

Millimeter wave treatment promotes chondrocyte proliferation via G1/S cell cycle transition

Millimeter wave treatment promotes chondrocyte proliferation via G1/S cell cycle transition

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Treatment of osteoarthritis with mesenchymal stem cells

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