Effect of Age on Regulation of Human Osteoclast Differentiation

Chung, Ping-Lin; Zhou, Shuanhu; Eslami, Bita; Shen, Longxiang; LeBoff, Meryl S.; Glowacki, Julie

doi:10.1002/jcb.24792

Cited by 84 publications

(68 citation statements)

References 46 publications

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“…The RANKL/OPG ratio is an indicator of regulation of osteoclast differentiation . For example, we found that the RANKL/OPG ratio in marrow stromal cells (MSCs) increased with the age of the study subject and was correlated with spontaneous in vitro generation of osteoclasts from marrow . In addition, the RANKL/OPG ratio from subjects receiving alendronate was half that for control subjects, and in vitro treatment of MSCs with alendronate reduced the RANKL/OPG ratio in a dose‐dependent manner .…”

Section: Discussionmentioning

confidence: 98%

Influence of osteoarthritis grade on molecular signature of human cartilage

Zhou

Thornhill

Meng³

et al. 2015

Journal Orthopaedic Research

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Articular chondrocytes maintain cartilage matrix turnover and have the capacity for anabolic and catabolic activities that can be influenced by injury and disease. This study tested the hypothesis that catabolic genes are upregulated with regional osteoarthritis (OA) disease severity within a joint. With IRB approval, specimens of knee cartilage obtained as discarded tissues from subjects undergoing arthroplasty were partitioned for each subject by OA disease severity and evaluated for gene expression by RT-PCR. There was regional OA grade-associated upregulation of expected inflammatory mediators TNF-a, TNF receptors, IFN-g, and interleukins as well as genes encoding proteolytic enzymes, including Adamts-5 and MMPs. Osteoclast-related genes, cathepsin K, tartrate-resistant acid phosphatase (TRAP), RANKL, RANK, M-CSF, and c-fms, but not osteoprotegerin, were induced in advanced grades. In vitro treatment of normal human chondrocytes with interleukin-1b upregulated similar genes; this provides evidence that chondrocytes per se can be the source of osteoclast-related factors. Immunohistochemical staining showed that RANK-and RANKLpositive cells were abundant in advanced grades, especially in chondrocyte clusters. This suggests a possible autocrine mechanism by which an osteoclast phenotype is induced in articular chondrocytes. In sum, these studies identified gene expression signatures in human OA cartilage based upon regional disease severity within a joint. There was an effect of OA Grade on expression of osteoclastic lytic enzymes and regulatory factors in human articular chondrocytes. Induction of an osteoclast-like phenotype in chondrocytes may be part of OA progression and suggests specific therapeutic approaches. ß

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Section: Discussionmentioning

confidence: 98%

Influence of osteoarthritis grade on molecular signature of human cartilage

Zhou

Thornhill

Meng³

et al. 2015

Journal Orthopaedic Research

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“…Loss of bone mass associated with human skeletal aging can be explained in part by the age-related decline in in vitro osteoblast differentiation [10–13,24] and by the age-related increase in in vitro osteoclast differentiation [64] with bone cell progenitors from bone marrow. Finding vitamin D-hydroxylases and regulated activity in hMSCs provides support for the hypothesis of an autocrine/paracrine role of vitamin D metabolism in human osteoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells

et al. 2013

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There are many human extra-renal tissues and cells that biosynthesize 1α,25-dihydroxyvitamin D (1α,25(OH)2D) by the action of CYP27B1/1α-hydroxylase. Human marrow stromal cells (hMSCs), also known as mesenchymal stem cells, were isolated from marrow discarded from well-characterized, consented subjects during common orthopedic procedures. Human MSCs can give rise to osteoblasts, chondrocytes, adipocytes, and other lineages. Their in vitro differentiation to osteoblasts is stimulated by 1α,25(OH)2D, and recent evidence indicates that they have the capacity to metabolize vitamin D in a regulated manner. Human MSCs express the vitamin D receptor, 25-hydroxylases, 1α-hydroxylase, and 24-hydroxylase; stimulation of in vitro osteoblastogenesis by 25(OH)D depends on the activity of CYP27B1/1α-hydroxylase. Finding that hMSCs are a both a producer and target of 1α,25(OH)2D suggests a potential autocrine/paracrine role of vitamin D metabolism in osteoblast differentiation. Expression and enzyme activity of CYP27B1/1α-hydroxylase are upregulated by substrate 25(OH)D and Parathyroid Hormone (PTH) and are downregulated by 1α,25(OH)2D. With subject age, there is a decrease in basal osteoblast potential and in stimulation of osteoblastogenesis by 1α,25(OH)2D, 25(OH)D, and PTH. In vitro treatment with a combination of 25(OH)D and PTH rejuvenated osteoblastogenesis with hMSCs from elders; this was attributable to increases in CYP27B1/1α-hydroxylase and in receptor for each hormone by the reciprocal factor. Other clinical variables beside age, i.e. low serum 25(OH)D or low estimated glomerular filtration rate, are correlated with reduced osteoblastogenesis. These studies suggest that osteoblastogenesis may not be optimal unless there is sufficient serum 25(OH)D substrate for hMSCs to synthesize and respond to local 1α,25(OH)2D.

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“…Skeletal homeostasis depends on multiple factors regulating bone remodeling, the cycle that consists of bone resorption by osteoclasts and new bone formation by osteoblasts. Emerging evidence from in vitro studies with human marrow stromal cells from young and old subjects shows an age-related decline in osteoblast differentiation potential in vitro [1, 2] and an age-related increase in ability to support osteoclastogenesis in vitro [3]. Little is known about the effects of age on in vitro hematopoiesis.…”

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confidence: 99%

Dysregulated in vitro hematopoiesis, radiosensitivity, proliferation, and osteoblastogenesis with marrow from SAMP6 mice

O'Sullivan

Greenberger

Goff

et al. 2012

Experimental Hematology

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The Senescence Accelerated-Prone mouse variant 6 (SAMP6) shows normal growth followed by rapid aging, development of osteopenia, and shortened lifespan, compared with control R1 mice. Because oxidative stress is a fundamental mechanism of tissue aging, we tested whether cellular parameters that are associated with oxidative stress are impaired with marrow from SAMP6 mice. We compared in vitro hematopoiesis, irradiation sensitivity, proliferative potential, and osteoblastogenesis with marrow cells from SAMP6 and R1 mice. Marrow cells from SAMP6 mice showed shortened in vitro hematopoiesis; their stromal cells showed greater radiation sensitivity and decreased proliferation. Consistent with those properties, there was constitutive upregulation of TGF-β1, an inhibitor of hematopoiesis, and of cell cycle inhibitory genes, p16INK4A and p19ARF. Paradoxically, there was constitutive expression of osteoblast genes in stromal cells from SAMP6 mice, but in vitro matrix mineralization was impaired. These studies and data included in other reports indicate that impaired proliferation of osteoblast progenitors in SAMP6 marrow may be a major factor contributing to accelerated loss of bone mass. In sum, marrow from SAMP6 mice had diminished capacity for long-term hematopoiesis, increased radiosensitivity, and reduced proliferative capacity.

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Effect of Age on Regulation of Human Osteoclast Differentiation

Cited by 84 publications

References 46 publications

Influence of osteoarthritis grade on molecular signature of human cartilage

Influence of osteoarthritis grade on molecular signature of human cartilage

Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells

Dysregulated in vitro hematopoiesis, radiosensitivity, proliferation, and osteoblastogenesis with marrow from SAMP6 mice

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