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Hyaluronan in normal and malignant bone marrow: a clinical and morphological study with emphasis on myelofibrosis
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibrosis in the bone marrow is usually denominated myelofibrosis and may contribute to impaired hematopoiesis. Myelofibrosis is seen both in malignant and non-malignant diseases.

The normal microenvironment in the bone marrow consists of a heterogenous population of hematopoietic and non-hematopoietic stromal cells, their extracellular products and hematopoietic cytokines. The stromal cells produce a complex array of molecules, among others collagens and glycosaminoglycans (GAGs) of which hyaluronan (HYA) is the most abundant. Marrow fibrosis results from an increased deposition of collagens, which are polypeptides. Staining for reticulin, mostly composed of collagen type III, is the common way of visualizing myelofibrosis. HYA, like the collagens, is widely distributed in connective tissues. Little is known about the distribution of HYA in bone marrow.

The aims of this thesis have been to determine how HYA is distributed in normal and malignant bone marrow, compared to reticulin staining, and to follow patients with chronic myeloproliferative diseases (CMPD) during two years treatment with anagrelide considering development of cellularity and fibrosis.

In bone marrow biopsies from healthy volunteers, the controls, HYA was found in a pattern that was concordant with the reticulin staining.

Comparing patients with different malignant diseases with and without bone marrow involvemen, HYA staining was found to be significantly stronger in both groups compared to the controls.

The HYA scores were also significantly higher in the bone marrow of patients with de novo acute myeloid leukemia (AML), compared to the controls.

There was a correlation between HYA and reticulin in the patients with de novo AML, and in the patients with different malignant diseases with and without bone marrow involvement as in the controls.

Increase of HYA, reticulin and cellularity in the bone marrow of patients with CMPD after two years of treatment with anagrelide indicated progression of fibrosis. Anagrelide is a valuable drug for reduction of platelets but seems unable to stop progression of fibrosis and hypercellularity.

HYA is an interesting molecule with properties not only contributing to the structure of extracellular matrix but also to cell signaling and behaviour, although the understanding of the detailed mechanisms is still incomplete.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin , 2005. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 997
Keyword [en]
Hyaluronan, reticulin, fibrosis, chronic myeloproliferative disorders, acute myeloid leukemia, anagrelide, bone marrow
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:umu:diva-658ISBN: 91-7305-990-0 (print)OAI: oai:DiVA.org:umu-658DiVA: diva2:144146
Public defence
2006-02-03, Sal D, Tandläkarhögskolan, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2005-12-15 Created: 2005-12-15 Last updated: 2009-10-08Bibliographically approved
List of papers
1. Localisation and distribution of hyaluronan in normal bone marrow matrix: a novel method to evaluate impending fibrosis?
Open this publication in new window or tab >>Localisation and distribution of hyaluronan in normal bone marrow matrix: a novel method to evaluate impending fibrosis?
2002 (English)In: European Journal of Haematology, ISSN 0902-4441, Vol. 68, no 4, 194-202 p.Article in journal (Refereed) Published
Abstract [en]

Bone marrow trephine biopsies from 30 healthy volunteers, 10 men and 20 women aged 18-60 yr were obtained for identification and localisation of hyaluronan (HYA). Fixation, decalcification and embedding were performed by two different methods, with identical results in both. For comparison bone marrow trephine biopsies from three patients with different haematological diseases and known fibrosis were studied. All bone marrow specimens were also stained for reticulin grading. HYA was found in the bone marrow specimens from healthy individuals in a pattern that was concordant with the reticulin staining, the common way of visualising bone marrow fibrosis. In bone marrow from the patients with known fibrosis the HYA and reticulin staining were both more intense and abundant. Interestingly, HYA was also found intracellularly in eosinophilic cells in normal bone marrow. HYA is a polysaccharide unique both in structural and biological properties, and in excess it may predict bone marrow fibrosis.

Identifiers
urn:nbn:se:umu:diva-4875 (URN)10.1034/j.1600-0609.2002.01617.x (DOI)12071934 (PubMedID)
Available from: 2005-12-15 Created: 2005-12-15Bibliographically approved
2. Hyaluronan in bone marrow in patients with various malignant disorders
Open this publication in new window or tab >>Hyaluronan in bone marrow in patients with various malignant disorders
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4876 (URN)
Available from: 2005-12-15 Created: 2005-12-15 Last updated: 2010-01-13Bibliographically approved
3. Bone marrow hyaluronan distribution in patients with acute myeloid leukemia.
Open this publication in new window or tab >>Bone marrow hyaluronan distribution in patients with acute myeloid leukemia.
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2005 (English)In: Medical Oncology, ISSN 1357-0560, Vol. 22, no 1, 71-78 p.Article in journal (Refereed) Published
Abstract [en]

The present study investigated potential age-related changes in human muscle spindles with respect to the intrafusal fiber-type content and myosin heavy chain (MyHC) composition in biceps brachii muscle. The total number of intrafusal fibers per spindle decreased significantly with aging, due to a significant reduction in the number of nuclear chain fibers. Nuclear chain fibers in old spindles were short and some showed novel expression of MyHC α-cardiac. The expression of MyHC α-cardiac in bag1 and bag2 fibers was greatly decreased in the A region. The expression of slow MyHC was increased in nuclear bag1 fibers and that of fetal MyHC decreased in bag2 fibers whereas the patterns of distribution of the remaing MyHC isoforms were generelly not affected by aging. We conclude that aging appears to have an important impact on muscle spindle composition. These changes in muscle spindle phenotype may reflect an age-related deterioration in sensory and motor innervation and are likely to have an impact in motor control in the elderly.

Keyword
Adult, Aged, Aged; 80 and over, Bone Marrow/*chemistry, Female, Humans, Hyaluronic Acid/*analysis, Immunohistochemistry, Leukemia; Myelocytic; Acute/*metabolism, Male, Middle Aged, Reticulin/analysis
Identifiers
urn:nbn:se:umu:diva-13170 (URN)10.1385/MO:22:1:071 (DOI)15750199 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-10-08Bibliographically approved
4. No effect of anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining
Open this publication in new window or tab >>No effect of anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4878 (URN)
Available from: 2005-12-15 Created: 2005-12-15 Last updated: 2010-01-13Bibliographically approved

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