Thomas L Andersen

University of Southern Denmark, Odense, South Denmark, Denmark

Are you Thomas L Andersen?

Claim your profile

Publications (49)222.32 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We would like to express our appreciation to the editorial board members and external reviewers, who have contributed a great deal to the high quality of this special issue. Meanwhile, we want to express our appreciation to the editor broad, who offers us great suggestions and supports in this special issue.
    Full-text · Article · Aug 2015 · International Journal of Endocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment. © 2015 John Wiley & Sons Ltd.
    No preview · Article · Jul 2015 · British Journal of Haematology
  • Source
    Christina M Andreasen · Ming Ding · Søren Overgaard · Peter Bollen · Thomas Levin Andersen
    [Show abstract] [Hide abstract]
    ABSTRACT: Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6mg/kg/day, 5 times weekly) for 7months. At 7months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces. In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Bone
  • [Show abstract] [Hide abstract]
    ABSTRACT: Successful bone remodeling demands that osteoblasts restitute the bone removed by osteoclasts. In human cancellous bone, a pivotal role in this restitution is played by the canopies covering the bone remodeling surfaces, since disruption of canopies in multiple myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with absence of progression of the remodeling cycle to bone formation, i.e. uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces. In postmenopausal osteoporosis, this concept is supported by the coincidence between absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis of iliac crest biopsies from patients exposed to long-term glucocorticoid treatment revealed a subpopulation of reversal surfaces corresponding to the characteristics of arrest found in postmenopausal osteoporosis. Importantly, these arrested reversal surfaces were devoid of canopy coverage in almost all biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports a model where bone restitution during remodeling demands recruitment of osteoprogenitors from the canopy onto reversal surfaces. These data suggest that securing the presence of functional local osteoprogenitors deserves attention in the search of strategies to prevent the bone loss that occurs during bone remodeling in pathological situations. Copyright © 2014. Published by Elsevier Inc.
    No preview · Article · Dec 2014 · Bone
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoblast recruitment during bone remodeling is obligatory to re-construct the bone resorbed by the osteoclast. This recruitment is believed to be triggered by osteoclast products and is therefore likely to start early during the remodeling cycle. Several osteoclast products with osteoblast recruitment potential are already known. Here we draw the attention on the osteoblast recruitment potential of the collagen that is freshly demineralized by the osteoclast. Our evidence is based on observations on adult human cancellous bone, combined with in vitro assays. First, freshly eroded surfaces where osteoblasts have to be recruited show the presence of non-degraded demineralized collagen and close cell-collagen interactions, as revealed by electron microscopy, while surface-bound collagen strongly attracts osteoblast lineage cells in a transmembrane migration assay. Compared with other extracellular matrix molecules, collagen's potency was superior and only equaled by fibronectin. Next, the majority of the newly recruited osteoblast lineage cells positioned immediately next to the osteoclasts, exhibit uPARAP/Endo180, an endocytic collagen receptor reported to be involved in collagen internalization and cell migration in various cell types, and whose inactivation is reported to lead to lack of bone formation and skeletal deformities. In the present study, an antibody directed against this receptor inhibits collagen internalization in osteoblast lineage cells and decreases to some extent their migration to surface-bound collagen in the transmembrane migration assay. These complementary observations lead to a model where collagen demineralized by osteoclasts attracts surrounding osteoprogenitors onto eroded surfaces, and where the endocytic collagen receptor uPARAP/Endo180 contributes to this migration, probably together with other collagen receptors. This model fits recent knowledge on the position of osteoprogenitor cells immediately next to remodeling sites in adult human cancellous bone.
    Full-text · Article · Jul 2014 · Bone
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is still unknown where from osteoblasts are recruited during remodeling of adult human cancellous bone. Still, it is often suggested that they originate from perivascular osteoprogenitors in the bone marrow (BM). Here we propose also the existence of a layer of osteoprogenitors at the periphery of the BM. This proposal is based on electron and light microscopy of the bone surface and of the neighboring BM in human iliac crest biopsies, where we quantified cell densities, cell proliferation, osteoblast differentiation markers, and capillaries (N=14) (Danish Ethical Committee S20070121). We found that quiescent surfaces are not only covered by bone lining cells, but also by very flat (< 0.1 μm) and elongated cells, which are P3NP-positive and surround the whole BM. At the level of osteoclasts, this cell envelope appears lifted forming a canopy over the remodeling site - a view which is supported by the physical continuity between this canopy and the BM envelope at the level of quiescent surfaces, and by the fact that the vast majority of osteoclast surfaces are covered by a canopy. Canopies proved to consist of osteoblast-lineage cells which are more proliferative and less differentiated than bone surface cells, as shown by the inverse levels of Ki-67 and P3NP versus osterix. Furthermore, the presence of capillarycanopy contacts peaked over osteoclast surfaces, and the number of capillary-canopy contacts correlated positively with the osteoblast density on bone-forming surfaces. Interestingly, canopy cell density was negatively affected by age, and correlated also positively with osteoblast density on bone-forming surfaces. In conclusion, the present data point to the BM envelope as a source of osteoprogenitors. Its dual interaction with osteoclasts and capillaries upon initiation of the bone remodeling cycle fits the current knowledge of the role of osteoclasts and vasculature in triggering osteogenesis.
    Full-text · Conference Paper · May 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone-remodeling compartments (BRCs) were recently recognized to be present in patients with primary hyperparathyroidism and critical for bone reconstruction in multiple myeloma and endogenous Cushing's syndrome. The BRCs are outlined by a cellular canopy separating the bone-remodeling events on the bone surface from the marrow cavity. The present study on human iliac crest biopsy specimens reveals that BRC canopies appear frequently absent above both eroded and formative surfaces in post-menopausal osteoporosis patients, and that this absence was associated with bone loss in these patients. The absence of BRC canopies above the eroded surfaces was furthermore associated with the accumulation of arrested reversal surfaces and a reduced extent of formative surfaces, which both reflect an increased incidence of aborted remodeling cycles. Moreover, the absence of BRC canopies above formative surfaces was associated with a shift in the osteoblast morphological characteristics, from cuboidal to flattened. Collectively, this study shows that the BRCs are unique anatomical structures implicated in bone remodeling in a widespread disease, such as post-menopausal osteoporosis. Furthermore, it particularly highlights the role of the BRC canopies to make the reversal phase progressing toward initiation of matrix deposition, thereby preventing bone loss.
    No preview · Article · Feb 2014 · American Journal Of Pathology

  • No preview · Conference Paper · Feb 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone-forming osteoblasts recruited during bone remodeling might originate from bone marrow perivascular cells, bone-remodeling compartment canopy cells, or bone-lining cells. However, an assessment of osteoblast recruitment during adult human cancellous bone remodeling is lacking. We addressed this question by quantifying cell densities, cell proliferation, osteoblast differentiation markers, and capillaries in human iliac crest biopsy specimens. We found that recruitment occurs on both reversal and bone-forming surfaces, as shown by the cell density and osterix levels on these respective surfaces, and bone formation occurs only above a given cell density. Next, canopies represent an important source of osteoprogenitors, because canopy cells proved to be more proliferative and less differentiated than bone surface cells, as shown by the inverse levels of Ki-67 and procollagen-3 N-terminal peptide versus osterix; and canopy cell densities, which decline with age, and canopy-capillary contacts above eroded surfaces correlated positively with osteoblast density on bone-forming surfaces. Bone-remodeling compartment canopies also arise from a mesenchymal envelope surrounding the red bone marrow, which is lifted and hypertrophied on initiation of bone resorption. This study, together with earlier reports, led to a model in which canopies and nearby capillaries are critical for reaching the osteoblast density required for bone formation.
    Full-text · Article · Jan 2014 · American Journal Of Pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is the physical site where coupling of bone resorption to bone formation occurs.
    Full-text · Article · Dec 2013 · Biochemical and Biophysical Research Communications
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Odanacatib (ODN) is a bone resorption inhibitor which differs from standard antiresorptives by its ability to reduce bone resorption without decreasing bone formation. What is the reason for this difference? In contrast with other antiresorptives, such as alendronate (ALN), ODN targets only the very last step of the resorption process. We hypothesize that ODN may therefore modify the remodeling events immediately following osteoclastic resorption. These events belong to the reversal phase and include recruitment of osteoblasts, which is critical for connecting bone resorption to formation. We performed a histomorphometric study of trabecular remodeling in vertebrae of estrogen-deficient rabbits treated or not with ODN or ALN, a model where ODN, but not ALN, was previously shown to preserve bone formation. In line with our hypothesis, we found that ODN treatment compared to ALN results in a shorter reversal phase, faster initiation of osteoid deposition on the eroded surfaces, and higher osteoblast recruitment. The latter is reflected by higher densities of mature bone forming osteoblasts and an increased subpopulation of cuboidal osteoblasts. Furthermore, we found an increase in the interface between osteoclasts and surrounding osteoblast-lineage cells. This increase is expected to favor the osteoclast-osteoblast interactions required for bone formation. Regarding bone resorption itself, we show that ODN, but not ALN, treatment results in shallower resorption lacunae, a geometry favoring bone stiffness. We conclude that, compared to standard antiresorptives, ODN shows distinctive effects on resorption geometry and on reversal phase activities which positively affect osteoblast recruitment and may therefore favor bone formation.
    Full-text · Article · Oct 2013 · Calcified Tissue International
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone remodeling requires bone resorption by osteoclasts, bone formation by osteoblasts, and a poorly investigated reversal phase coupling resorption to formation. Likely players of the reversal phase are the cells recruited into the lacunae vacated by the osteoclasts and presumably preparing these lacunae for bone formation. These cells, called herein reversal cells, cover >80% of the eroded surfaces, but their nature is not identified, and it is not known whether malfunction of these cells may contribute to bone loss in diseases such as postmenopausal osteoporosis. Herein, we combined histomorphometry and IHC on human iliac biopsy specimens, and showed that reversal cells are immunoreactive for factors typically expressed by osteoblasts, but not for monocytic markers. Furthermore, a subpopulation of reversal cells showed several distinctive characteristics suggestive of an arrested physiological status. Their prevalence correlated with decreased trabecular bone volume and osteoid and osteoblast surfaces in postmenopausal osteoporosis. They were, however, virtually absent in primary hyperparathyroidism, in which the transition between bone resorption and formation occurs optimally. Collectively, our observations suggest that arrested reversal cells reflect aborted remodeling cycles that did not progress to the bone formation step. We, therefore, propose that bone loss in postmenopausal osteoporosis does not only result from a failure of the bone formation step, as commonly believed, but also from a failure at the reversal step.
    Full-text · Article · Jun 2013 · American Journal Of Pathology
  • Thomas Levin Andersen · Helene Bjorg Kristensen · Jean-Marie Delaisse

    No preview · Article · May 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vascularization is a prerequisite for osteogenesis in a number of situations, including bone development, fracture healing, and cortical bone remodeling. It is unknown whether a similar link exists between cancellous bone remodeling and vascularization. Here, we show an association between remodeling sites, capillaries, proliferative cells and putative osteoblast progenitors. Iliac crest biopsies from normal human individuals were subjected to histomorphometry and immunohistochemistry to identify the respective positions of bone remodeling sites, CD34-positive capillaries, smooth muscle actin (SMA)-positive putative osteoblast progenitors, including pericytes, Ki67-positive proliferative cells, and bone remodeling compartment (BRC) canopies. The BRC canopy is a recently described structure separating remodeling sites from the bone marrow, consisting of CD56-positive osteoblasts at an early differentiation stage. We found that bone remodeling sites were associated with a significantly increased presence of capillaries, putative osteoblast progenitors and proliferative cells in a region within 50 µm of the bone or the canopy surface. The increases were the highest above eroded surfaces and at the level of the light-microscopically assessed contact of these three entities with the bone or canopy surfaces. Between 51 and 100 µm, their densities leveled to that found above quiescent surfaces. Electron microscopy asserted the close proximity between BRC canopies and capillaries lined by pericytes. Furthermore, the BRC canopy cells were found to express SMA. These ordered distributions support the existence of an osteogenic-vascular interface in adult human cancellous bone. The organization of this interface fits the current knowledge on the mode of action of vasculature on osteogenesis, and points to the BRC canopy as a central player in this mechanism. We propose a model where initiation of bone remodeling coincides with the induction of proximity of the vasculature to endosteal surfaces, thereby allowing capillary-BRC canopy interactions that activate marrow events, including recruitment of osteoblast progenitors to bone remodeling sites. © 2012 American Society for Bone and Mineral Research.
    No preview · Article · Mar 2013 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A remarkable property of bone remodeling is that osteoblasts form bone matrix exactly where and when osteoclasts have removed it. The bone remodeling compartment (BRC) canopies that cover bone surfaces undergoing remodeling were proposed to be critical players in this mechanism. Here, we provide support to this hypothesis by analyzing the changes in prevalence of BRC canopies during the progress of the remodeling cycle in a cohort of healthy individuals and in patients with endogenous Cushing's syndrome (CS), and by relating these changes in prevalence with the extent of bone forming surfaces. Both cohorts showed almost 100% canopy coverage above resorbing osteoclasts, and only about 76% above bone forming surfaces. This indicates that BRC canopies are invariably associated with the early stage of the remodeling cycle, but may disappear later. Interestingly, in control and two-thirds of the CS patients, a significant decline in canopy coverage occurred only once bone formation was initiated, but in the remaining third of the CS patients the prevalence of canopies already decreased before bone formation. This canopy loss before initiation of bone formation coincided with significantly less bone-forming surface compared with canopy loss at a later stage. These observations support a model where bone restitution is compromised in the absence of BRC canopies, and apparently does not start when the BRC canopy is lost before initiation of the bone formation step. This model is discussed in the context of possible biological roles of BRC canopies. It suggests that BRC canopies could be privileged targets for treating patients suffering from a negative bone formation-resorption balance.
    Full-text · Article · Apr 2012 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Marie-Louise Bastholm Bille · Bjarke Thomsen · Thomas Levin Andersen · Inger Kjær
    [Show abstract] [Hide abstract]
    ABSTRACT: Root resorption, impaired tooth eruption and early tooth loss have been described in relation to diseases that involve defects in the RANK-RANKL-OPG-expression. The aim of the present immunhistochemical study was to localize and compare the reactions for RANK and membrane-bound RANKL along root surfaces and in the periodontal membrane in close proximity to the root surface of human primary and permanent teeth. The material comprised extracted human teeth (11 primary teeth and six permanent teeth) from 10 different patients. Paraffin sections were prepared of each tooth and sections of each tooth were immunohistochemically stained with antibodies specific for membrane-bound RANKL and RANK. The root surface and the periodontal membrane in close proximity to the root surface did not show immunoreactivity for RANKL. RANKL was only located in odontoblasts and in cells along denticles in one primary tooth. RANK was located in mononuclear cells in the pulp and in multinucleated odontoclasts along resorbed root surfaces and along resorbed dentin surfaces in the pulp in primary teeth and one permanent tooth. This study demonstrated RANK positivity in resorption areas in primary and permanent teeth. RANKL was positive in the pulp of one primary tooth. RANK expression in odontoclasts and RANKL expression in the pulp may indicate that RANK/RANKL play a role during resorption.
    No preview · Article · Mar 2012 · Acta odontologica Scandinavica
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence. Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF). The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length. These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.
    Full-text · Article · Jan 2012 · Arthritis research & therapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoclasts are terminally differentiated leukocytes that erode the mineralized bone matrix. Osteoclastogenesis requires costimulatory receptor signaling through adaptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), such as Fc receptor common γ (FcRγ) and DNAX-activating protein of 12 kDa. Identification of these ITAM-containing receptors and their ligands remains a high research priority, since the stimuli for osteoclastogenesis are only partly defined. Osteoclast-associated receptor (OSCAR) was proposed to be a potent FcRγ-associated costimulatory receptor expressed by preosteoclasts in vitro, but OSCAR lacks a cognate ligand and its role in vivo has been unclear. Using samples from mice and patients deficient in various ITAM signaling pathways, we show here that OSCAR costimulates one of the major FcRγ-associated pathways required for osteoclastogenesis in vivo. Furthermore, we found that OSCAR binds to specific motifs within fibrillar collagens in the ECM that become revealed on nonquiescent bone surfaces in which osteoclasts undergo maturation and terminal differentiation in vivo. OSCAR promoted osteoclastogenesis in vivo, and OSCAR binding to its collagen motif led to signaling that increased numbers of osteoclasts in culture. Thus, our results suggest that ITAM-containing receptors can respond to exposed ligands in collagen, leading to the functional differentiation of leukocytes, which provides what we believe to be a new concept for ITAM regulation of cytokine receptors in different tissue microenvironments.
    Full-text · Article · Aug 2011 · The Journal of clinical investigation

  • No preview · Article · May 2011 · Bone

  • No preview · Article · Apr 2011 · Bone

Publication Stats

1k Citations
222.32 Total Impact Points

Institutions

  • 2004-2015
    • University of Southern Denmark
      • Institute of Regional Health Research
      Odense, South Denmark, Denmark
  • 2012
    • Sygehus Lillebaelt
      Vejle, South Denmark, Denmark
  • 2011
    • Bispebjerg Hospital, Copenhagen University
      København, Capital Region, Denmark
  • 2005-2010
    • Odense University Hospital
      • Department of Endocrinology - M
      Odense, South Denmark, Denmark
  • 2009
    • University of Southern Mississippi
      HBG, Mississippi, United States
  • 2004-2007
    • Nordic Bioscience
      København, Capital Region, Denmark
  • 2002-2004
    • Center for Clinical and Basic Research
      København, Capital Region, Denmark