The Experts below are selected from a list of 87 Experts worldwide ranked by ideXlab platform
Clifford J. Rosen - One of the best experts on this subject based on the ideXlab platform.
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the role of zfp467 in mediating the pro osteogenic and anti adipogenic effects on Bone and Bone marrow niche
Bone, 2021Co-Authors: Hanghang Liu, Lama Alabdulaaly, Yosta Vegting, Isabella L Calle, Francesca Gori, Beate Lanske, Roland Baron, Clifford J. RosenAbstract:Conditional deletion of the PTH receptor (Pth1r) in mesenchymal progenitors reduces osteoblast differentiation and Bone mass while enhancing adipogenesis and Bone marrow adipose tissue. Mechanistically, PTH suppresses the expression of Zfp467, a pro-adipogenic zinc finger transcription factor. Consequently, Pth1r deficiency in mesenchymal progenitors leads to increased Zfp467 expression. Based on these observations, we hypothesized that genetic loss of Zfp467 would lead to a shift in marrow progenitor cell fate towards osteogenesis and increased Bone mass. To test this hypothesis, we generated Zfp467-/- mice. Zfp467-/- mice (-/-) were significantly smaller than Zfp467+/+ mice (+/+). μCT showed significantly higher trabecular Bone and cortical Bone area in -/- vs. +/+, and histomorphometry showed higher structural and dynamic formation parameters in -/- mice vs. +/+. Femoral gene expression including Alpl, Sp7, and Acp5 were increased in -/-mice, whereas Adiponectin, Cebpa, Lepr, and Ppraγ mRNA were lower in -/- mice. Similarly, Fabp4 and Lep in the inguinal depot were also decreased in -/- mice. Moreover, marrow adipocyte numbers were reduced in -/- vs +/+ mice (p<0.007). In vitro, COBs and BMSCs-/- showed more positive ALP and Alizarin Red staining and a decrease in ORO droplets. Pth1r mRNA and protein levels were increased in COBs and BMSCs from -/- mice vs +/+ (p<0.02 for each parameter, -/- vs. +/+). -/- cells also exhibited enhanced endogenous levels of cAMP vs. control cells. Moreover, in an ovariectomy (OVX) mouse model, Zfp467-/- mice had significantly lower fat mass but similar Bone mass compared to OVX +/+ mice. In contrast, in a high fat diet (HFD) mouse model, in addition to reduced adipocyte volume and adipogenesis related gene expression in both peripheral and Bone marrow fat tissue, greater osteoblast number and higher osteogenesis related gene expression were also observed in -/- HFD mice vs. +/+ HFD mice. Taken together, these results demonstrate that ZFP467 negatively influences skeletal homeostasis and favors adipogenesis. Global deletion of Zfp467 increases PTHR1, cAMP and Bone turnover, hence its repression is a component of PTH signaling and its regulation. These data support a critical role for Zfp467 in early lineage allocation and provide a novel potential mechanism by which PTH acts in an anabolic manner on the Bone Remodeling Unit.
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The Epidemiology and Pathogenesis of Osteoporosis
2014Co-Authors: Clifford J. RosenAbstract:Osteoporosis is a multifactorial disorder associated with low Bone mass and enhanced skeletal fragility. Although most prevalent in older females, some men are also at high risk. Risk factors in men and women include smoking, family history of fracture, age greater than 65 years, and low but also high BMI particularly in men. Secondary causes of osteoporosis include chronic treatment with glucocorticoids, gastrointestinal disorders, diabetes mellitus (T1D, T2D), rheumatoid arthritis, liver disease, gluten enteropathy, multiple myeloma and other hematologic disorders. However, primary osteoporosis is most often related to either postmenopausal estrogen loss or age-related deterioration of skeletal microarchitecture; both are due to uncoupling in the Bone Remodeling Unit. Reduced Bone formation with age is almost certainly a function of impaired stem cell differentiation into the osteoblast lineage with a resultant increase in marrow adipogenesis. Increased Bone resorption also characterizes most forms of osteoporosis but the etiology is multifactorial. Changes in local and systemic growth factors are often responsible for uncoupling between resorption and formation. However, alterations in peak Bone acquisition contribute years later to low Bone mass and enhanced skeletal fragility. Fracture risk assessment tools (e.g. FRAX) in handheld apps and computers which combine Bone density score and risk factors, have provided rapid assessments of future osteoporotic fractures and can be performed at the bedside. Newer methods of measuring Bone quality have led to insights into micro-architectural deterioration that contributes to skeletal fragility. Notwithstanding, low areal Bone mineral density by DEXA remains the strongest predictor of subsequent fracture beyond age, and this is potentially measurable in everyone after age 65. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .
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IGF-1 regulation of key signaling pathways in Bone.
BoneKEy reports, 2013Co-Authors: Anyonya R. Guntur, Clifford J. RosenAbstract:Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is Bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligand-receptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the Bone Remodeling Unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.
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Vitamin D and Bone Health in Adults and the Elderly
1999Co-Authors: Clifford J. RosenAbstract:Vitamin D is one of the principle hormonal regulators of calcium homeostasis in the body. Besides being critically important for calcium and phosphate absorption in the intestine, vitamin D is essential for normal mineralization of Bone and has major regulatory effects on Bone cells in the Bone Remodeling Unit. In addition to distant skeletal and intestinal effects, the active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], also regulates its own synthesis in the kidney and parathyroid hormone (PTH) secretion in the parathyroid gland. These multisystem effects firmly establish the importance of this hormone in the maintenance of skeletal health. Moreover, perturbations in vitamin D synthesis, secretion, or action have been implicated as potential pathogenetic factors in the development of osteoporosis. For these reasons, there has been sustained interest in vitamin D and 1,25(OH)2D3 as therapeutic agents in several metabolic Bone disorders. However, the relationship between active vitamin D and its metabolites and calcified tissue components is complex and redundant. Hence a thorough understanding of the role vitamin D plays in the Bone Remodeling process (either directly or indirectly) is extremely important. In turn, complete delineation of the physiologic role of vitamin D in mineral homeostasis illustrates why vitamin D deficiency, especially in the elderly, is now being recognized as a major public health issue.
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THE PATHOPHYSIOLOGY AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS An Evidence-Based Approach to Estrogen Replacement Therapy
Endocrinology and metabolism clinics of North America, 1997Co-Authors: Clifford J. Rosen, Cathy R. KessenichAbstract:Osteoporosis is one of the most common and debilitating diseases of postmenopausal women. Recent advances in understanding the Bone Remodeling Unit have clarified the pathophysiologic processes that contribute to Bone loss after the onset of estrogen deprivation. Epidemiologic studies have suggested a protective effect from long-term estrogen replacement therapy on fracture risk. This article examines the key role estrogens play in Bone Remodeling and the current evidence that estrogen treatment in postmenopausal women reduces the likelihood of osteoporotic fractures.
D. W. Dempster - One of the best experts on this subject based on the ideXlab platform.
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Bone modeling and Remodeling: potential as therapeutic targets for the treatment of osteoporosis.
Therapeutic advances in musculoskeletal disease, 2016Co-Authors: Bente L. Langdahl, Serge Ferrari, D. W. DempsterAbstract:The adult skeleton is renewed by Remodeling throughout life. Bone Remodeling is a process where osteoclasts and osteoblasts work sequentially in the same Bone Remodeling Unit. After the attainment of peak Bone mass, Bone Remodeling is balanced and Bone mass is stable for one or two decades until age-related Bone loss begins. Age-related Bone loss is caused by increases in resorptive activity and reduced Bone formation. The relative importance of cortical Remodeling increases with age as cancellous Bone is lost and Remodeling activity in both compartments increases. Bone modeling describes the process whereby Bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based Bone formation contributes to the periosteal expansion, just as Remodeling-based resorption is responsible for the medullary expansion seen at the long Bones with aging. Existing and upcoming treatments affect Remodeling as well as modeling. Teriparatide stimulates Bone formation, 70% of which is Remodeling based and 20-30% is modeling based. The vast majority of modeling represents overflow from Remodeling Units rather than de novo modeling. Denosumab inhibits Bone Remodeling but is permissive for modeling at cortex. Odanacatib inhibits Bone resorption by inhibiting cathepsin K activity, whereas modeling-based Bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates Bone formation and histomorphometric analysis demonstrated that Bone formation is predominantly modeling based. The Bone-mass response to some osteoporosis treatments in humans certainly suggests that nonRemodeling mechanisms contribute to this response and Bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that rediscovering a phenomenon that was first observed more half a century ago will have an important impact on our understanding of how new antifracture treatments work.
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On the mechanism of cancellous Bone preservation in postmenopausal women with mild primary hyperparathyroidism.
The Journal of clinical endocrinology and metabolism, 1999Co-Authors: D. W. Dempster, May Parisien, Shonni J. Silverberg, X. G. Liang, M. Schnitzer, V. Shen, Elizabeth Shane, Donald B. Kimmel, Robert R. Recker, R. LindsayAbstract:Several studies have demonstrated that cancellous Bone mass and architecture are preserved in postmenopausal women with primary hyperparathyroidism (PHPT). To investigate the mechanism(s) that could account for this observation, we analyzed features of Bone formation in 19 postmenopausal women with PHPT by Bone histomorphometry. The results were compared with those from a comparable group of 34 healthy, postmenopausal women. Patients with PHPT were similar to control subjects in cancellous Bone area as well as in trabecular width, separation, and number. However, in PHPT, elevations were observed in indexes of Bone turnover, such as eroded surface, osteoid surface, mineralizing surface, Bone formation rate at the tissue level, and activation frequency. At the level of the Bone-Remodeling Unit, women with PHPT had significantly higher values for the wall width of trabecular Bone packets (40.26 +/- 0.36 vs. 34.58 +/- 0.45 mm), the adjusted apposition rate (0.40 +/- 0.04 vs. 0.29 +/- 0.03 mm/day), and the active formation period (67.8 +/- 5.1 vs. 57.3 +/- 2.3 days). These findings are consistent with a stimulatory action of elevated PTH levels on the duration of the active Bone formation phase in individual Remodeling Units and may account at least in part for the preservation of cancellous Bone in postmenopausal women with mild PHPT.
Cathy R. Kessenich - One of the best experts on this subject based on the ideXlab platform.
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THE PATHOPHYSIOLOGY AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS An Evidence-Based Approach to Estrogen Replacement Therapy
Endocrinology and metabolism clinics of North America, 1997Co-Authors: Clifford J. Rosen, Cathy R. KessenichAbstract:Osteoporosis is one of the most common and debilitating diseases of postmenopausal women. Recent advances in understanding the Bone Remodeling Unit have clarified the pathophysiologic processes that contribute to Bone loss after the onset of estrogen deprivation. Epidemiologic studies have suggested a protective effect from long-term estrogen replacement therapy on fracture risk. This article examines the key role estrogens play in Bone Remodeling and the current evidence that estrogen treatment in postmenopausal women reduces the likelihood of osteoporotic fractures.
Lidan You - One of the best experts on this subject based on the ideXlab platform.
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measuring Bone cell response to fluid shear stress and hydrostatic dynamic pressure
Experimental Methods in Orthopaedic Biomechanics, 2017Co-Authors: Kevin Middleton, Lidan YouAbstract:Abstract Mechanical stimulation of Bone regulates Bone Remodeling via Wolff's Law, which can be applied to Bone disorders (e.g., osteoporosis) to improve Bone strength. Tissue level loading of Bone transduces to cellular forces in a complex manner. Bone-forming osteoblasts follow Bone-resorbing osteoclasts in a Bone Remodeling Unit and are exposed to fluid shear stresses. Mechanosensing osteocytes reside within a lacunar–canalicular space and are exposed to fluid flow, hydrostatic pressure, and strain. Bone marrow stromal cells (BMSCs) reside within the marrow and undergo intramedullary pressures, along with intermedullary and interstitial fluid flow. Understanding Bone cell responses to mechanical stimulation helps identify signaling pathways and cellular interactions for Bone homeostasis, thus leading to new therapies for Bone disorders. Therefore, this chapter explains how to perform in vitro mechanical stimulation tests on Bone cells, as well as how to analyze, present, and interpret results.
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Measuring Bone Cell Response to Fluid Shear Stress and Hydrostatic/Dynamic Pressure
Experimental Methods in Orthopaedic Biomechanics, 2017Co-Authors: Kevin Middleton, Lidan YouAbstract:Abstract Mechanical stimulation of Bone regulates Bone Remodeling via Wolff's Law, which can be applied to Bone disorders (e.g., osteoporosis) to improve Bone strength. Tissue level loading of Bone transduces to cellular forces in a complex manner. Bone-forming osteoblasts follow Bone-resorbing osteoclasts in a Bone Remodeling Unit and are exposed to fluid shear stresses. Mechanosensing osteocytes reside within a lacunar–canalicular space and are exposed to fluid flow, hydrostatic pressure, and strain. Bone marrow stromal cells (BMSCs) reside within the marrow and undergo intramedullary pressures, along with intermedullary and interstitial fluid flow. Understanding Bone cell responses to mechanical stimulation helps identify signaling pathways and cellular interactions for Bone homeostasis, thus leading to new therapies for Bone disorders. Therefore, this chapter explains how to perform in vitro mechanical stimulation tests on Bone cells, as well as how to analyze, present, and interpret results.
Pierre D. Delmas - One of the best experts on this subject based on the ideXlab platform.
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BIOCHEMICAL MARKERS OF Bone TURNOVER: Applications For Osteoporosis
Endocrinology and metabolism clinics of North America, 1998Co-Authors: Patrick Garnero, Pierre D. DelmasAbstract:Osteoporosis is a disease characterized by low Bone mass and by architectural deterioration of Bone tissue, two factors related to abnormalities of Bone turnover. Histomorphometric studies of iliac crest biopsies suggest that decreased Bone mass is caused by distinct abnormalities, including an imbalance between Bone resorption and Bone formation within a Remodeling Unit (owing to increased osteoclastic activity with or without decreased osteoblastic activity) and an increase in the activation frequency of the number of Remodeling Units initiated per Unit of time. The small negative balance within each Bone Remodeling Unit is amplified by the overall increase in Bone turnover, which is highly variable from patient to patient. It is generally believed that the increase in activation frequency is directly dependent on estrogen deficiency in postmenopausal women, whereas Remodeling imbalance might be related to a combination of age-related factors such as a decrease of insulin-like growth factor 1 (IGF-1) production. Secondary hyperparathyroidism, which is highly prevalent in the elderly, especially in persons with vitamin D deficiency, probably worsens the increase in Bone turnover related to estrogen deficiency. Biochemical markers of Bone turnover reflect the degree of increase in overall Bone turnover, and, thus far, no data indicate that the levels of markers of Bone formation and resorption can be combined to assess Remodeling imbalance. The rate of Bone formation or degradation can be assessed either by measuring an enzymatic activity of the osteoblastic or osteoclastic cells, such as alkaline and acid phosphatase activity, or by measuring components of the Bone matrix released into the circulation during formation or resorption, such as osteocalcin and pyridinoline cross-links (Table 1). In osteoporosis, Bone turnover markers have been suggested to predict the rate of postmenopausal Bone loss and the occurrence of osteoporotic fractures and may be useful in monitoring the efficacy of treatment, especially antiresorptive therapy (e.g., hormone replacement therapy, bisphosphonates, and calcitonin). Measurement of Bone turnover before treatment might be useful to select the type of therapy (antiresorptive or Bone-stimulating agent) and to predict the amplitude of the response to estrogen and bisphosphonate treatment, however, there is no solid evidence for these two concepts. This article reviews recent developments in Bone marker technology and discusses the use of these markers for the management of osteoporosis.