J. P. T. M. Van Leeuwen (original) (raw)

Papers by J. P. T. M. Van Leeuwen

Osteoarthritis and Cartilage, 2008

Objective: To see how initial differences in subchondral bone phenotype influence the development... more Objective: To see how initial differences in subchondral bone phenotype influence the development of cartilage damage and changes in subchondral bone architecture in an osteoarthritis (OA)-induced mouse model. Method: Intra-articular collagenase injections (right knee joint) and saline controls (left knee joint) were applied in the knees of two mouse strains known to have either a low or a high bone mass phenotype: the low bone mass C57Bl/6 mice with a thin subchondral bone plate and high bone mass C3H/HeJ mice with a thick subchondral bone plate. The ages of the mice were 16 and 30 weeks, with n ¼ 8 per group. The collagenase injection induced an osteoarthritic phenotype that was evaluated 4 weeks later in the tibia using histological analyses and micro-computed tomography (micro-CT). Results: Both strains developed cartilage damage in the collagenase-injected right knee joints to a comparable extent, however, the spatial distribution of cartilage damage differed significantly: C57Bl/6 mice had most damage at the postero-lateral side, whereas in C3H/HeJ mice the postero-medial region was the most affected. Spontaneous cartilage damage was found in the saline-injected left control knees of C57Bl/6 mice, but in C3H/HeJ mice spontaneous cartilage damage was virtually absent. In both strains the subchondral bone plate of collagenaseinjected joints became thinner, independent of the site of cartilage damage. TRAP-positive osteoclasts were observed underneath the subchondral bone plate, in line with the observed decreased thickness. No link was found between subchondral bone plate thickness and cartilage damage in the collagenase-injected joints. The subchondral trabecular architecture only changed in the high bone mass C3H/ HeJ mice, with thinning of trabeculae and increased trabecular spacing. Conclusion: Thinning of the subchondral bone plate was found as a common observation 4 weeks after OA had been induced in two strains of mice having either a high or low bone phenotype, but no relation was found with the amount of cartilage damage. In addition, this study shows that different strains of mice can react differently to instability-induced OA with respect to the spatial arrangement of cartilage damage and changes in subchondral trabecular structure.

Osteoarthritis and Cartilage, 2008

Objective: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of... more Objective: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of 50. Animal models are used to study the effects of hormone depletion [by ovariectomy (OVX)] and estrogen treatment on OA. This review summarizes these animal studies, in order to get a better insight in the role of hormones on OA. Method: The literature was systematically reviewed until May 2007. The results were divided into two parts: the effect of OVX on cartilage, and the effect of estrogen treatment on cartilage. Only studies with an appropriate control group (e.g., sham-operated) were included. Results and discussion: Eleven out of 16 animal studies showed that OVX resulted in cartilage damage. When only studies using sexually mature animals were included, we saw that 11 out of 14 studies showed a detrimental effect, indicating considerable evidence for a relation between cartilage degeneration and OVX in mature animals. The effect of estrogen treatment was inconclusive with only 11 out of 22 animal studies reporting a beneficial effect on cartilage, whereas all six studies administering selective estrogen receptor modulators (SERMs) after OVX described protective effects. The discrepancy between the studies may be caused by the large variation in experimental setup. We suggested a list of quality criteria for animal models since standardisation of design and outcome parameters of animal experiments may help to compare different studies and to gain better insight in the role of hormones in the osteoarthritic process.

Endocrinology, 1995

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to inhibit breast cancer cell growth both ... more 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to inhibit breast cancer cell growth both in vitro and in vivo. A major drawback is that high doses of 1,25-(OH)2D3 are needed which may result in undesirable side effects like the development of hypercalcemia and an increased risk of bone metastases due to the stimulation of bone resorption by 1,25-(OH)2D3. Several newly developed 1,25-(OH)2D3 analogs have a reduced calcemic activity, but their direct effects on bone resorption have not yet been examined. Presently, the antiestrogen tamoxifen is the most important endocrine therapy for breast cancer. Recent studies have demonstrated the benefit of the combination tamoxifen and 1,25-(OH)2D3/analogs for the inhibition of breast cancer cell growth. Besides inhibition of breast cancer growth tamoxifen appeared to have beneficial effects on bone. The purpose of the present study was to investigate the effect of tamoxifen on 1,25-(OH)2D3- and analogs (EB1089 and KH1060)-stimulated bone resorption in an in vitro model. Bone resorption was stimulated by 1,25-(OH)2D3 and analogs in a dose-dependent manner with KH1060 and EB1089 being more potent and 1,25-(OH)2D3. Tamoxifen caused a strong dose-dependent inhibition (70% at 10 microM) of 1,25-(OH)2D3- and EB1089-stimulated bone resorption. KH1060-stimulated bone resorption was also inhibited by tamoxifen but to a lesser extent (36%). Also the pure antiestrogen ICI164,384 but not 17 beta-estradiol inhibited 1,25-(OH)2D3-stimulated bone resorption. Together, this study demonstrates that tamoxifen considerably reduces 1,25-(OH)2D3/analogs-stimulated bone resorption and therefore may be useful to reduce the risk of bone metastases. This together with the observed beneficial effects on breast cancer cell growth indicates that tamoxifen together with 1,25-(OH)2D3/analogs is an interesting combination for the treatment of breast cancer. The mechanism of the bone resorption inhibitory action is not yet known but seems to be independent of the estrogen pathway.

AGE, 2010

The increasing average age in developed societies is paralleled by an increase in the prevalence ... more The increasing average age in developed societies is paralleled by an increase in the prevalence of many age-related diseases such as osteoarthritis (OA), which is characterized by deformation of the joint due to cartilage damage and increased turnover of subchondral bone. Consequently, deficiency in DNA repair, often associated with premature aging, may lead to increased pathology of these two tissues. To examine this possibility, we analyzed the bone and cartilage phenotype of male and female knee joints derived from 52-to 104-week-old WT C57Bl/6 and trichothiodystrophy (TTD) mice, who carry a defect in the nucleotide excision repair pathway and display many features of premature aging. Using micro-CT, we found bone loss in all groups of 104-week-old compared to 52-week-old mice. Cartilage damage was mild to moderate in all mice. Surprisingly, female TTD mice had less cartilage damage, proteoglycan depletion, and osteophytosis compared to WT controls. OA severity in males did not significantly differ between genotypes, although TTD males had less osteophytosis. These results indicate that in premature aging TTD mice age-related changes in cartilage were not more severe compared to WT mice, in striking contrast with bone and many other tissues. This segmental aging character may be explained by a difference in vasculature and thereby oxygen load in cartilage and bone. Alternatively, a difference in impact of an anti-aging response, previously found to be triggered by accumulation of DNA damage, might help explain why female mice were protected from cartilage damage. These findings underline the exceptional segmental nature of progeroid conditions and provide an explanation for pro-and anti-aging features occurring in the same individual.

BMC musculoskeletal disorders, Jan 23, 2007

Tendinosis lesions show an increase of glycosaminoglycan amount, calcifications, and lipid accumu... more Tendinosis lesions show an increase of glycosaminoglycan amount, calcifications, and lipid accumulation. Therefore, altered cellular differentiation might play a role in the etiology of tendinosis. This study investigates whether adolescent human tendon tissue contains a population of cells with intrinsic differentiation potential. Cells derived from adolescent non-degenerative hamstring tendons were characterized by immunohistochemistry and FACS-analysis. Cells were cultured for 21 days in osteogenic, adipogenic, and chondrogenic medium and phenotypical evaluation was carried out by immunohistochemical and qPCR analysis. The results were compared with the results of similar experiments on adult bone marrow-derived stromal cells (BMSCs). Tendon-derived cells stained D7-FIB (fibroblast-marker) positive, but alpha-SMA (marker for smooth muscle cells and pericytes) negative. Tendon-derived cells were 99% negative for CD34 (endothelial cell marker), and 73% positive for CD105 (mesenchym...

Journal of cellular physiology, 2017

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bo... more Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. Identification of factors influencing osteoblast differentiation and bone formation is very important. Previously, we identified parbendazole to be a novel compound that stimulates osteogenic differentiation of human mesenchymal stromal cells (hMSCs), using gene expression profiling and bioinformatic analyzes, including the Connectivity Map (CMap), as an in-silico approach. The aim for this paper is to identify additional compounds affecting osteoblast differentiation using the CMap. Gene expression profiling was performed on hMSCs differentiated to osteoblasts using Illumina microarrays. Our osteoblast gene signature, the top regulated genes 6 hr after induction by dexamethasone, was uploaded into CMap (www.broadinstitute.org/cmap/). Through this approach we identified compounds with gene signatures positively correlating (withaferin-A, calcium ...

Bone, 2014

We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of... more We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23 years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alo...

Osteoarthritis and Cartilage, 2007

Journal of Cellular Physiology, 2012

Osteoimmunology is an emerging field of research focused on the interaction of the immune system ... more Osteoimmunology is an emerging field of research focused on the interaction of the immune system and bone. In this study we demonstrate that human osteoblasts are sensitive to the immune cytokine interferon (IFN)b. Osteoblasts respond to IFNb as shown by the induction of several known IFN target genes such as interferon-induced (IFI) proteins (IFIT1, IFI44L), interferon-stimulated gene factor 3 (ISGF3) complex and the induction of IFNb itself. We demonstrated that IFNb has severe inhibitory effects on mineralization of osteoblast-derived extracellular matrix (ECM). Analysis of the timing of the IFNb effects revealed that committed osteoblasts in early stage of differentiation are most sensitive to IFNb inhibition of mineralization. A single IFNb treatment was as effective as multiple treatments. During the progress of differentiation osteoblasts become desensitized for IFNb. This pinpoints to a complex pattern of IFNb sensitivity in osteoblasts. Focusing on early osteoblasts, we showed that IFNb decreased gene expression of ECM-related genes, such as type I Collagen (COL1A1), fibronectin (FN1), fibullin (FBLN1), fibrillin (FBN2), and laminin (LAMA1). Additionally, ECM produced by IFNb-treated osteoblasts contained less collagen protein. IFNb stimulated gene expression of osteopontin (OPN), annexin2 (ANXA2), and hyaluronan synthase 1 (HAS1), which are important factors in the adhesion of hematopoietic stem cells (HSC) in the HSC niche. In conclusion, IFNb directly modifies human osteoblast function by inhibiting ECM synthesis eventually resulting in delayed bone formation and mineralization and induces a HSC niche supporting phenotype. These effects are highly dependent on timing of treatment in the early phase of osteoblast differentiation.

BioFactors, 2013

Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially ... more Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially characterized as a growth hormone (GH) secretagogue, but it plays a more important role as a potent orexigen and modulator of whole-body energy homeostasis. Ghrelin itself is closely regulated by metabolic status. Bone remodeling constantly renews the skeleton in a highly energy-dependent fashion. Accordingly, bone metabolism is tightly coupled to energy metabolism through the integration of peripheral and central mechanisms, involving the sympathetic nervous system and factors such as leptin. Ghrelin has been shown to modulate osteoblast differentiation and function, both directly and perhaps also through regulation of the GH-insulin-like growth factor axis. However, recently it has also been shown that ghrelin interacts with leptin in modulating bone structure, constituting a new mechanism that couples bone metabolism with energy homeostasis. In this review, we discuss the role that ghrelin plays modulating bone cell function, and its integrative role in coupling bone metabolism with energy metabolism.

Arthritis & Rheumatism, 2003

Objective. To study the association between prevalent radiographic osteoarthritis (ROA) of the kn... more Objective. To study the association between prevalent radiographic osteoarthritis (ROA) of the knee and incident vertebral and nonvertebral fractures. Methods. A sample of 2,773 subjects was drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. Status on knee ROA was assessed at baseline using the Kellgren score. Incident nonvertebral fractures were scored for all subjects, and for 1,466 subjects additional data on incident vertebral fractures were available. Results. Although people with ROA had a higher bone mineral density (BMD), their incident fracture risk was increased as compared with those without ROA. After adjustment for potential confounding factors, including parameters of postural stability, the relative risks for incident vertebral and nonvertebral fractures in the presence of knee ROA were 2.0 (95% confidence interval [95% CI] 1.1-3.4) and 1.5 (95% CI 1.1-2.0), respectively. Conclusions: Knee ROA is associated with an increased risk of incident vertebral and nonvertebral fractures, independent of BMD and parameters of postural stability.

Journal of Proteome Research, 2011

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2015

In the present study, the possibility that a diabetic (DM) status might worsen age-related bone d... more In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.

Osteoarthritis and Cartilage, 2006

Purpose: To evaluate a semi-automated paired cartilage segmentation algorithm for the assessment ... more Purpose: To evaluate a semi-automated paired cartilage segmentation algorithm for the assessment of cartilage volume, surface area and thickness. Methods: Unilateral knee MR images of 12 subjects (6 healthy, 6 with clinical osteoarthritis (OA) of the knee) from an Osteoarthritis Initiative (OAI) pilot study were obtained. Each subject was imaged twice to permit measurement of repositioning reproducibility. 3D DESS (sagittal, 0.365mm x 0.365mm, 0.7mm slice thickness, TR 16.5msec, TE 4.7msec) images were obtained on a 3 Tesla Siemens Trio with a USA Instruments quadrature transmit-receive extremity coil. In the first segmentation session we evaluated each acquisition and measured cartilage morphometry independent of any prior information. In the second round, image pairs were viewed concurrently in two adjacent windows. After manual registration of the segmented contours, the first segmentation results served as the Quality Control of the second segmentation. Cartilage edge identification was accomplished by an automated software algorithm based on predetermined greyscale differences between the surrounding soft tissue and bone. We evaluated cartilage morphometry measures of the bone and cartilage surface area (SA), cartilage volume and thickness for medial/lateral tibia, total femur and patella. The root-mean square coefficient of variation (RMS CV) was used as a metric to quantify the test-retest reproducibility. Results: For the paired analyses RMS CV ranged from 0.9% to 1.2% for volume, from 0.3% to 0.7% for cartilage SA, from 0.6% to 2.7% for the bone SA and 0.8% to 1.5% for thickness (Table 1). Poster Presentations These data indicate that changes in thickness of the subchondral bone plate in post-traumatic osteoarthritis as modeled here develop in a biphasic manner, with initial thinning followed by subsequent thickening.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2015

In the present study, the possibility that a diabetic (DM) status might worsen age-related bone d... more In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.

Osteoarthritis and Cartilage, 2008

Objective: To see how initial differences in subchondral bone phenotype influence the development... more Objective: To see how initial differences in subchondral bone phenotype influence the development of cartilage damage and changes in subchondral bone architecture in an osteoarthritis (OA)-induced mouse model. Method: Intra-articular collagenase injections (right knee joint) and saline controls (left knee joint) were applied in the knees of two mouse strains known to have either a low or a high bone mass phenotype: the low bone mass C57Bl/6 mice with a thin subchondral bone plate and high bone mass C3H/HeJ mice with a thick subchondral bone plate. The ages of the mice were 16 and 30 weeks, with n ¼ 8 per group. The collagenase injection induced an osteoarthritic phenotype that was evaluated 4 weeks later in the tibia using histological analyses and micro-computed tomography (micro-CT). Results: Both strains developed cartilage damage in the collagenase-injected right knee joints to a comparable extent, however, the spatial distribution of cartilage damage differed significantly: C57Bl/6 mice had most damage at the postero-lateral side, whereas in C3H/HeJ mice the postero-medial region was the most affected. Spontaneous cartilage damage was found in the saline-injected left control knees of C57Bl/6 mice, but in C3H/HeJ mice spontaneous cartilage damage was virtually absent. In both strains the subchondral bone plate of collagenaseinjected joints became thinner, independent of the site of cartilage damage. TRAP-positive osteoclasts were observed underneath the subchondral bone plate, in line with the observed decreased thickness. No link was found between subchondral bone plate thickness and cartilage damage in the collagenase-injected joints. The subchondral trabecular architecture only changed in the high bone mass C3H/ HeJ mice, with thinning of trabeculae and increased trabecular spacing. Conclusion: Thinning of the subchondral bone plate was found as a common observation 4 weeks after OA had been induced in two strains of mice having either a high or low bone phenotype, but no relation was found with the amount of cartilage damage. In addition, this study shows that different strains of mice can react differently to instability-induced OA with respect to the spatial arrangement of cartilage damage and changes in subchondral trabecular structure.

Osteoarthritis and Cartilage, 2008

Objective: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of... more Objective: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of 50. Animal models are used to study the effects of hormone depletion [by ovariectomy (OVX)] and estrogen treatment on OA. This review summarizes these animal studies, in order to get a better insight in the role of hormones on OA. Method: The literature was systematically reviewed until May 2007. The results were divided into two parts: the effect of OVX on cartilage, and the effect of estrogen treatment on cartilage. Only studies with an appropriate control group (e.g., sham-operated) were included. Results and discussion: Eleven out of 16 animal studies showed that OVX resulted in cartilage damage. When only studies using sexually mature animals were included, we saw that 11 out of 14 studies showed a detrimental effect, indicating considerable evidence for a relation between cartilage degeneration and OVX in mature animals. The effect of estrogen treatment was inconclusive with only 11 out of 22 animal studies reporting a beneficial effect on cartilage, whereas all six studies administering selective estrogen receptor modulators (SERMs) after OVX described protective effects. The discrepancy between the studies may be caused by the large variation in experimental setup. We suggested a list of quality criteria for animal models since standardisation of design and outcome parameters of animal experiments may help to compare different studies and to gain better insight in the role of hormones in the osteoarthritic process.

Endocrinology, 1995

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to inhibit breast cancer cell growth both ... more 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to inhibit breast cancer cell growth both in vitro and in vivo. A major drawback is that high doses of 1,25-(OH)2D3 are needed which may result in undesirable side effects like the development of hypercalcemia and an increased risk of bone metastases due to the stimulation of bone resorption by 1,25-(OH)2D3. Several newly developed 1,25-(OH)2D3 analogs have a reduced calcemic activity, but their direct effects on bone resorption have not yet been examined. Presently, the antiestrogen tamoxifen is the most important endocrine therapy for breast cancer. Recent studies have demonstrated the benefit of the combination tamoxifen and 1,25-(OH)2D3/analogs for the inhibition of breast cancer cell growth. Besides inhibition of breast cancer growth tamoxifen appeared to have beneficial effects on bone. The purpose of the present study was to investigate the effect of tamoxifen on 1,25-(OH)2D3- and analogs (EB1089 and KH1060)-stimulated bone resorption in an in vitro model. Bone resorption was stimulated by 1,25-(OH)2D3 and analogs in a dose-dependent manner with KH1060 and EB1089 being more potent and 1,25-(OH)2D3. Tamoxifen caused a strong dose-dependent inhibition (70% at 10 microM) of 1,25-(OH)2D3- and EB1089-stimulated bone resorption. KH1060-stimulated bone resorption was also inhibited by tamoxifen but to a lesser extent (36%). Also the pure antiestrogen ICI164,384 but not 17 beta-estradiol inhibited 1,25-(OH)2D3-stimulated bone resorption. Together, this study demonstrates that tamoxifen considerably reduces 1,25-(OH)2D3/analogs-stimulated bone resorption and therefore may be useful to reduce the risk of bone metastases. This together with the observed beneficial effects on breast cancer cell growth indicates that tamoxifen together with 1,25-(OH)2D3/analogs is an interesting combination for the treatment of breast cancer. The mechanism of the bone resorption inhibitory action is not yet known but seems to be independent of the estrogen pathway.

AGE, 2010

The increasing average age in developed societies is paralleled by an increase in the prevalence ... more The increasing average age in developed societies is paralleled by an increase in the prevalence of many age-related diseases such as osteoarthritis (OA), which is characterized by deformation of the joint due to cartilage damage and increased turnover of subchondral bone. Consequently, deficiency in DNA repair, often associated with premature aging, may lead to increased pathology of these two tissues. To examine this possibility, we analyzed the bone and cartilage phenotype of male and female knee joints derived from 52-to 104-week-old WT C57Bl/6 and trichothiodystrophy (TTD) mice, who carry a defect in the nucleotide excision repair pathway and display many features of premature aging. Using micro-CT, we found bone loss in all groups of 104-week-old compared to 52-week-old mice. Cartilage damage was mild to moderate in all mice. Surprisingly, female TTD mice had less cartilage damage, proteoglycan depletion, and osteophytosis compared to WT controls. OA severity in males did not significantly differ between genotypes, although TTD males had less osteophytosis. These results indicate that in premature aging TTD mice age-related changes in cartilage were not more severe compared to WT mice, in striking contrast with bone and many other tissues. This segmental aging character may be explained by a difference in vasculature and thereby oxygen load in cartilage and bone. Alternatively, a difference in impact of an anti-aging response, previously found to be triggered by accumulation of DNA damage, might help explain why female mice were protected from cartilage damage. These findings underline the exceptional segmental nature of progeroid conditions and provide an explanation for pro-and anti-aging features occurring in the same individual.

BMC musculoskeletal disorders, Jan 23, 2007

Tendinosis lesions show an increase of glycosaminoglycan amount, calcifications, and lipid accumu... more Tendinosis lesions show an increase of glycosaminoglycan amount, calcifications, and lipid accumulation. Therefore, altered cellular differentiation might play a role in the etiology of tendinosis. This study investigates whether adolescent human tendon tissue contains a population of cells with intrinsic differentiation potential. Cells derived from adolescent non-degenerative hamstring tendons were characterized by immunohistochemistry and FACS-analysis. Cells were cultured for 21 days in osteogenic, adipogenic, and chondrogenic medium and phenotypical evaluation was carried out by immunohistochemical and qPCR analysis. The results were compared with the results of similar experiments on adult bone marrow-derived stromal cells (BMSCs). Tendon-derived cells stained D7-FIB (fibroblast-marker) positive, but alpha-SMA (marker for smooth muscle cells and pericytes) negative. Tendon-derived cells were 99% negative for CD34 (endothelial cell marker), and 73% positive for CD105 (mesenchym...

Journal of cellular physiology, 2017

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bo... more Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. Identification of factors influencing osteoblast differentiation and bone formation is very important. Previously, we identified parbendazole to be a novel compound that stimulates osteogenic differentiation of human mesenchymal stromal cells (hMSCs), using gene expression profiling and bioinformatic analyzes, including the Connectivity Map (CMap), as an in-silico approach. The aim for this paper is to identify additional compounds affecting osteoblast differentiation using the CMap. Gene expression profiling was performed on hMSCs differentiated to osteoblasts using Illumina microarrays. Our osteoblast gene signature, the top regulated genes 6 hr after induction by dexamethasone, was uploaded into CMap (www.broadinstitute.org/cmap/). Through this approach we identified compounds with gene signatures positively correlating (withaferin-A, calcium ...

Bone, 2014

We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of... more We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23 years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alo...

Osteoarthritis and Cartilage, 2007

Journal of Cellular Physiology, 2012

Osteoimmunology is an emerging field of research focused on the interaction of the immune system ... more Osteoimmunology is an emerging field of research focused on the interaction of the immune system and bone. In this study we demonstrate that human osteoblasts are sensitive to the immune cytokine interferon (IFN)b. Osteoblasts respond to IFNb as shown by the induction of several known IFN target genes such as interferon-induced (IFI) proteins (IFIT1, IFI44L), interferon-stimulated gene factor 3 (ISGF3) complex and the induction of IFNb itself. We demonstrated that IFNb has severe inhibitory effects on mineralization of osteoblast-derived extracellular matrix (ECM). Analysis of the timing of the IFNb effects revealed that committed osteoblasts in early stage of differentiation are most sensitive to IFNb inhibition of mineralization. A single IFNb treatment was as effective as multiple treatments. During the progress of differentiation osteoblasts become desensitized for IFNb. This pinpoints to a complex pattern of IFNb sensitivity in osteoblasts. Focusing on early osteoblasts, we showed that IFNb decreased gene expression of ECM-related genes, such as type I Collagen (COL1A1), fibronectin (FN1), fibullin (FBLN1), fibrillin (FBN2), and laminin (LAMA1). Additionally, ECM produced by IFNb-treated osteoblasts contained less collagen protein. IFNb stimulated gene expression of osteopontin (OPN), annexin2 (ANXA2), and hyaluronan synthase 1 (HAS1), which are important factors in the adhesion of hematopoietic stem cells (HSC) in the HSC niche. In conclusion, IFNb directly modifies human osteoblast function by inhibiting ECM synthesis eventually resulting in delayed bone formation and mineralization and induces a HSC niche supporting phenotype. These effects are highly dependent on timing of treatment in the early phase of osteoblast differentiation.

BioFactors, 2013

Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially ... more Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially characterized as a growth hormone (GH) secretagogue, but it plays a more important role as a potent orexigen and modulator of whole-body energy homeostasis. Ghrelin itself is closely regulated by metabolic status. Bone remodeling constantly renews the skeleton in a highly energy-dependent fashion. Accordingly, bone metabolism is tightly coupled to energy metabolism through the integration of peripheral and central mechanisms, involving the sympathetic nervous system and factors such as leptin. Ghrelin has been shown to modulate osteoblast differentiation and function, both directly and perhaps also through regulation of the GH-insulin-like growth factor axis. However, recently it has also been shown that ghrelin interacts with leptin in modulating bone structure, constituting a new mechanism that couples bone metabolism with energy homeostasis. In this review, we discuss the role that ghrelin plays modulating bone cell function, and its integrative role in coupling bone metabolism with energy metabolism.

Arthritis & Rheumatism, 2003

Objective. To study the association between prevalent radiographic osteoarthritis (ROA) of the kn... more Objective. To study the association between prevalent radiographic osteoarthritis (ROA) of the knee and incident vertebral and nonvertebral fractures. Methods. A sample of 2,773 subjects was drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. Status on knee ROA was assessed at baseline using the Kellgren score. Incident nonvertebral fractures were scored for all subjects, and for 1,466 subjects additional data on incident vertebral fractures were available. Results. Although people with ROA had a higher bone mineral density (BMD), their incident fracture risk was increased as compared with those without ROA. After adjustment for potential confounding factors, including parameters of postural stability, the relative risks for incident vertebral and nonvertebral fractures in the presence of knee ROA were 2.0 (95% confidence interval [95% CI] 1.1-3.4) and 1.5 (95% CI 1.1-2.0), respectively. Conclusions: Knee ROA is associated with an increased risk of incident vertebral and nonvertebral fractures, independent of BMD and parameters of postural stability.

Journal of Proteome Research, 2011

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

EAI Endorsed Transactions on Pervasive Health and Technology, 2019

INTRODUCTION: Twitter has played an important role in the social life of people. The health-relat... more INTRODUCTION: Twitter has played an important role in the social life of people. The health-related tweets are extracted and find the spread of epidemic disease on network. It can provide as a starting place of individual data to learn the physical condition of users. OBJECTIVES: Key objective is to develop graph-based algorithm to detect public health in online social network. METHODS: The proposed method collect the tweets relating to general health in twitter using the min-cut algorithm. The algorithm finds the minimum cut off an undirected edge-weighted graph. The runtime of the algorithm seems to be faster than other graph algorithms. Min-cut is reliable and good in network optimization and prevents redundancy. RESULTS: To evaluate the performance, we utilize the health dataset on the detection of epidemic disease. The proposed method using a graph-based algorithm is the best in terms of accuracy, precision, and recall. With respect to the confusion matrix, Min-cut provides the highest true positive when compared to Text rank and K-Means algorithm. CONCLUSION: Proposed health detection method using graph-based algorithm is better than Text Rank and K-Means in all aspects.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2015

In the present study, the possibility that a diabetic (DM) status might worsen age-related bone d... more In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.

Osteoarthritis and Cartilage, 2006

Purpose: To evaluate a semi-automated paired cartilage segmentation algorithm for the assessment ... more Purpose: To evaluate a semi-automated paired cartilage segmentation algorithm for the assessment of cartilage volume, surface area and thickness. Methods: Unilateral knee MR images of 12 subjects (6 healthy, 6 with clinical osteoarthritis (OA) of the knee) from an Osteoarthritis Initiative (OAI) pilot study were obtained. Each subject was imaged twice to permit measurement of repositioning reproducibility. 3D DESS (sagittal, 0.365mm x 0.365mm, 0.7mm slice thickness, TR 16.5msec, TE 4.7msec) images were obtained on a 3 Tesla Siemens Trio with a USA Instruments quadrature transmit-receive extremity coil. In the first segmentation session we evaluated each acquisition and measured cartilage morphometry independent of any prior information. In the second round, image pairs were viewed concurrently in two adjacent windows. After manual registration of the segmented contours, the first segmentation results served as the Quality Control of the second segmentation. Cartilage edge identification was accomplished by an automated software algorithm based on predetermined greyscale differences between the surrounding soft tissue and bone. We evaluated cartilage morphometry measures of the bone and cartilage surface area (SA), cartilage volume and thickness for medial/lateral tibia, total femur and patella. The root-mean square coefficient of variation (RMS CV) was used as a metric to quantify the test-retest reproducibility. Results: For the paired analyses RMS CV ranged from 0.9% to 1.2% for volume, from 0.3% to 0.7% for cartilage SA, from 0.6% to 2.7% for the bone SA and 0.8% to 1.5% for thickness (Table 1). Poster Presentations These data indicate that changes in thickness of the subchondral bone plate in post-traumatic osteoarthritis as modeled here develop in a biphasic manner, with initial thinning followed by subsequent thickening.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2015

In the present study, the possibility that a diabetic (DM) status might worsen age-related bone d... more In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.