In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1-34) fragment

Stanislaus, Dinesh; Yang, Xiaonan; Liang, J.; Wolfe, J; Cain, R L; Onyia, Jude E.; Falla, N; Marder, Philip; Bidwell, Joseph P.; Queener, Stephen W.; Hock, Janet M.

doi:10.1016/s8756-3282(00)00309-4

Cited by 67 publications

(35 citation statements)

References 28 publications

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“…(17,38) It was shown that intermittent PTH administration transiently increased numbers of apoptotic osteoblasts and osteocytes in rat trabecular bone, but no protection from apoptosis was observed during the course of PTH treatment. (39) This study found that PTH did not regulate the apoptosis-related gene Bcl2. Similar findings were shown in a microarray study that compared gene expression in bone between continuous and intermittent PTH administration.…”

Section: Fig 5 Intermittent Pth Increased Bone Mass In Bcl2mentioning

confidence: 74%

Role of Bcl2 in Osteoclastogenesis and PTH Anabolic Actions in Bone

Yamashita

Datta

Chun

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:Introduction: B-cell leukemia/lymphoma 2 (Bcl2) is a proto-oncogene best known for its ability to suppress cell death. However, the role of Bcl2 in the skeletal system is unknown. Bcl2 has been hypothesized to play an important anti-apoptotic role in osteoblasts during anabolic actions of PTH. Although rational, this has not been validated in vivo; hence, the impact of Bcl2 in bone remains unknown. Materials and Methods: The bone phenotype of Bcl2 homozygous mutant (Bcl2

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Section: Fig 5 Intermittent Pth Increased Bone Mass In Bcl2mentioning

confidence: 74%

Role of Bcl2 in Osteoclastogenesis and PTH Anabolic Actions in Bone

Yamashita

Datta

Chun

et al. 2008

Journal of Bone and Mineral Research

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“…Increased osteoblast apoptosis also impairs bone formation in myeloma bone disease (42). Conversely, reduced osteoblast apoptosis may enhance bone formation (43,44).…”

Section: Discussionmentioning

confidence: 99%

Diabetes Enhances mRNA Levels of Proapoptotic Genes and Caspase Activity, Which Contribute to Impaired Healing

et al. 2006

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We previously reported that after a bacteria-induced wound in the scalp, type 2 diabetic (db/db) mice had higher levels of apoptosis of fibroblasts and bone-lining cells that are critical for healing compared with normoglycemic controls. To investigate mechanisms by which this might occur, RNA profiling and caspase activity was measured after inoculation of Porphyromonas gingivalis. Diabetes caused a more than twofold induction of 71 genes that directly or indirectly regulate apoptosis and significantly enhanced caspase-8, -9, and -3 activity. The functional significance of diabetes-induced apoptosis was studied by treating diabetic mice with a pancaspase inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone). Inhibiting apoptosis significantly improved several parameters of healing, including fibroblast density, enhanced mRNA levels of collagen I and III, and increased matrix formation. Improvements were also noted in bone, with an increase in the number of bone-lining cells and new bone formation. Thus, diabetes-enhanced apoptosis represents an important mechanism through which healing is impaired, and this can be explained, in part, by diabetes-increased expression of proapoptotic genes and caspase activity. Diabetes 55: 487-495, 2006 D iabetes affects Ͼ18 million Americans and causes significant morbidity and mortality (1). Diabetes complications that are debilitating include poor wound healing (2). The impaired healing affects the resolution of both acute and chronic wounds (3), which represent a significant health care burden in the U.S. As an example, ulcerations of the lower extremities, which heal poorly in diabetic patients, are a significant cause of hospitalization and are usually the first step in limb amputation (4). Of the 18 million people in the U.S. with diabetes, 20% will at some point develop ulcers that heal poorly (5,6).Healing of wounds in diabetes is characterized by delays in the repair process as well as a decrease in the tensile strength of healing wounds (3,7). Deficiencies in fibroblast numbers have been reported to represent an important aspect of delayed wound healing in diabetes (8 -10). It has been suggested that aberrant growth factor expression, altered inflammatory responses, or enhanced glycosylation of proteins may be involved (8,11,12). Alternatively, enhanced apoptosis may decrease fibroblast numbers, which could contribute to impaired diabetic healing (13). Whatever the cause, the generation and maintenance of a sufficient number of fibroblasts to participate in wound repair may be particularly important in diabetes. Humans with type 1 diabetes have impaired osseous healing (14). That this may be caused by reduced bone formation is supported by findings that serum osteocalcin levels are significantly lower in type 1 diabetic patients (15), and there is a reduction in osteoblast numbers and function (16 -18). In type 2 diabetes, there is evidence of diminished bone formation, increased risk of fracture, and impaired healing, but the mechanisms are not we...

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“…In contrast to the evidence for an anti-apoptotic effect of intermittent PTH on osteoblasts in the remodeling secondary spongiosa of adult mice, Stanislaus et al reported a 50% increase in apoptotic osteoblasts in the primary spongiosa of the distal femur of 1 month old rats after 7 and 21 days, but not after 28 days, of PTH injections [53]. The percentage of osteoblasts exhibiting TUNEL staining was not reported, and the phenomenon was not examined in the remodeling secondary spongiosa.…”

Section: Effect Of Intermittent Pth On Osteoblast Apoptosismentioning

confidence: 94%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

623

531

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Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

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In vivo regulation of apoptosis in metaphyseal trabecular bone of young rats by synthetic human parathyroid hormone (1-34) fragment

Cited by 67 publications

References 28 publications

Role of Bcl2 in Osteoclastogenesis and PTH Anabolic Actions in Bone

Role of Bcl2 in Osteoclastogenesis and PTH Anabolic Actions in Bone

Diabetes Enhances mRNA Levels of Proapoptotic Genes and Caspase Activity, Which Contribute to Impaired Healing

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

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