| 1. |
- Embree, Mildred C, et al.
(författare)
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Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis.
- 2010
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 176, s. 812-826
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Tidskriftsartikel (refereegranskat)abstract
- The temporomandibular joint is critical for jaw movements and allows for mastication, digestion of food, and speech. Temporomandibular joint osteoarthritis is a degenerative disease that is marked by permanent cartilage destruction and loss of extracellular matrix (ECM). To understand how the ECM regulates mandibular condylar chondrocyte (MCC) differentiation and function, we used a genetic mouse model of temporomandibular joint osteoarthritis that is deficient in two ECM proteins, biglycan and fibromodulin (Bgn(-/0) Fmod(-/-)). Given the unavailability of cell lines, we first isolated primary MCCs and found that they were phenotypically unique from hyaline articular chondrocytes isolated from the knee joint. Using Bgn(-/0) Fmod(-/-) MCCs, we discovered the early basis for temporomandibular joint osteoarthritis arises from abnormal and accelerated chondrogenesis. Transforming growth factor (TGF)-beta1 is a growth factor that is critical for chondrogenesis and binds to both biglycan and fibromodulin. Our studies revealed the sequestration of TGF-beta1 was decreased within the ECM of Bgn(-/0)Fmod(-/-) MCCs, leading to overactive TGF-beta1 signal transduction. Using an explant culture system, we found that overactive TGF-beta1 signals induced chondrogenesis and ECM turnover in this model. We demonstrated for the first time a comprehensive study revealing the importance of the ECM in maintaining the mandibular condylar cartilage integrity and identified biglycan and fibromodulin as novel key players in regulating chondrogenesis and ECM turnover during temoporomandibular joint osteoarthritis pathology.
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| 2. |
- Flores Bjurström, Carmen, et al.
(författare)
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Osteoclasts are not crucial for hematopoietic stem cell maintenance in adult mice
- 2013
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 98:12, s. 1848-1855
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Tidskriftsartikel (refereegranskat)abstract
- The osteoclast is vital for establishment of normal hematopoiesis in the developing animal. However, its role for maintenance of hematopoiesis in adulthood is more controversial. To shed more light on this process, we transplanted hematopoietic stem cells from two osteopetrotic mouse models, with lack of osteoclasts or defective osteoclast function, to normal adult mice and examined the bone phenotype and hematopoiesis in the recipients. B6SJL mice were lethally irradiated and subsequently transplanted with oc/oc, Receptor Activator of Nuclear Factor Kappa B knockout or control fetal liver cells. Osteoclasts derived from the recipient animals were tested in vitro for osteoclastogenesis and resorptive function. Bone remodeling changes were assessed using biomarkers of bone tumrnover and micro-CT. Hematopoiesis was assessed by flow cytometry and colony formation, and hematopoietic stem cell function by secondary competitive transplantations and cell cycle analysis. After transplantation, a donor chimerism of 97-98% was obtained, and by 15 weeks mild osteopetrosis had developed in recipients of cells from osteopetrotic mice. There were no alterations in the number of bone marrow cells. Colony formation was slightly reduced in Receptor Activator of Nuclear Factor Kappa B knock-out recipients but unchanged in oc/oc recipients. Phenotypically, stem cells were marginally reduced in recipients of cells from osteopetrotic mice, but no significant difference was seen in cell cycle status and in competitive secondary transplantations all three groups performed equally well. Our results indicate that osteoclast function is not crucial for hematopoietic stem cell maintenance in adult mice.
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| 3. |
- Henriksen, Kim, et al.
(författare)
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Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Osteopetrosis caused by defective acid secretion by the osteoclast, is characterized by defective bone resorption, increased osteoclast numbers, while bone formation is normal or increased. In contrast the bones are of poor quality, despite this uncoupling of formation from resorption. To shed light on the effect of uncoupling in adult mice with respect to bone strength, we transplanted irradiated three-month old normal mice with hematopoietic stem cells from control or oc/oc mice, which have defective acid secretion, and followed them for 12 to 28 weeks. Engraftment levels were assessed by flow cytometry of peripheral blood. Serum samples were collected every six weeks for measurement of bone turnover markers. At termination bones were collected for mu CT and mechanical testing. An engraftment level of 98% was obtained. From week 6 until termination bone resorption was significantly reduced, while the osteoclast number was increased when comparing oc/oc to controls. Bone formation was elevated at week 6, normalized at week 12, and reduced onwards. mu CT and mechanical analyses of femurs and vertebrae showed increased bone volume and bone strength of cortical and trabecular bone. In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength.
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| 4. |
- Henriksen, Kim, et al.
(författare)
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The future of blood-based biomarkers for Alzheimer's disease.
- 2014
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 10:1, s. 115-131
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
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| 5. |
- Thudium, Christian, et al.
(författare)
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A Comparison of Osteoclast-Rich and Osteoclast-Poor Osteopetrosis in Adult Mice Sheds Light on the Role of the Osteoclast in Coupling Bone Resorption and Bone Formation
- 2014
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 95:1, s. 83-93
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Tidskriftsartikel (refereegranskat)abstract
- Osteopetrosis due to lack of acid secretion by osteoclasts is characterized by abolished bone resorption, increased osteoclast numbers, but normal or even increased bone formation. In contrast, osteoclast-poor osteopetrosis appears to have less osteoblasts and reduced bone formation, indicating that osteoclasts are important for regulating osteoblast activity. To illuminate the role of the osteoclast in controlling bone remodeling, we transplanted irradiated skeletally mature 3-month old wild-type mice with hematopoietic stem cells (HSCs) to generate either an osteoclast-rich or osteoclast-poor adult osteopetrosis model. We used fetal liver HSCs from (1) oc/oc mice, (2) RANK KO mice, and (3) compared these to wt control cells. TRAP5b activity, a marker of osteoclast number and size, was increased in the oc/oc recipients, while a significant reduction was seen in the RANK KO recipients. In contrast, the bone resorption marker CTX-I was similarly decreased in both groups. Both oc/oc and Rank KO recipients developed a mild osteopetrotic phenotype. However, the osteoclast-rich oc/oc recipients showed higher trabecular bone volume (40 %), increased bone strength (66 %), and increased bone formation rate (54 %) in trabecular bone, while RANK KO recipients showed only minor trends compared to control recipients. We here show that maintaining non-resorbing osteoclasts, as opposed to reducing the osteoclasts, leads to increased bone formation, bone volume, and ultimately higher bone strength in vivo, which indicates that osteoclasts are sources of anabolic molecules for the osteoblasts.
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