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Journal of Bone and Mineral Research | 2001

Osteoblast Apoptosis and Bone Turnover

Janet M. Hock; Venkatesh Krishnan; Jude E. Onyia; Joseph P. Bidwell; J. Milas; D. Stanislaus

With the discoveries of different death mechanisms, an emerging definition of apoptosis is the process of cell death associated with caspase activation or caspase‐mediated cell death. This definition accepts that caspases represent the final common mechanistic pathway in apoptosis. Apoptosis may be triggered either by activation events that target mitochondria or endoplasmic reticulum or by activation of cell surface “death receptors,” for example, those in the tumor necrosis factor (TNF) superfamily. In the postnatal and adult skeleton, apoptosis is integral to physiological bone turnover, repair, and regeneration. The balance of osteoblast proliferation, differentiation, and apoptosis determines the size of the osteoblast population at any given time. Although apoptosis has been recorded in many studies of bone, the selective mechanisms invoked in the different models studied rarely have been identified. This review offers a broad overview of the current general concepts and controversies in apoptosis research and then considers specific examples of osteoblast apoptosis pertinent to skeletal development and to the regulation of bone turnover. In reviewing selected work on interdigital apoptosis in the developing skeleton, we discuss the putative roles of the bone morphogenetic proteins (BMPs), Msx2, RAR‐γ, and death inducer obliterator 1 (DIO‐1). In reviewing factors regulating apoptosis in the postnatal skeleton, we discuss roles of cytokines, growth factors, members of the TNF pathway, and the extracellular matrix (ECM). Finally, the paradoxical effects of parathyroid hormone (PTH) on osteoblast apoptosis in vivo are considered in the perspective of a recent hypothesis speculating that this may be a key mechanism to explain the anabolic effects of the hormone. An improved understanding of the apoptotic pathways and their functional outcomes in bone turnover and fracture healing may facilitate development of more targeted therapeutics to control bone balance in patients with osteoporosis and other skeletal diseases.


Bone | 1995

In vivo, human parathyroid hormone fragment (hPTH 1–34) transiently stimulates immediate early response gene expression, but not proliferation, in trabecular bone cells of young rats

Jude E. Onyia; Joseph P. Bidwell; J. Herring; J. Hulman; Janet M. Hock

Intermittent PTH increases trabecular bone mass in vivo by stimulating osteoblast differentiation to increase bone formation. The molecular events that mediate the anabolic effect of PTH on osteoblasts have not been characterized. We investigated if PTH regulated mRNA expression of proto-oncogenes, c-fos, c-jun, and c-myc, early response genes that have been shown to be involved in the regulation of both cell proliferation and differentiation. As PTH also regulates the early expression of the cytokine, interleukin-6 (IL-6), in bone cells in vitro, we also investigated if this occurred in vivo, in concert with the other early response genes. Northern blot hybridization was used to analyze mRNA expression in the metaphysis of the distal femur of young rats. To determine the proliferative state in these femurs, mRNA expression of the cell proliferation marker histone, H4, was assessed. Subcutaneous administration of a single injection of human PTH (1-34) at 8 micrograms/100 g, a dose known to increase bone forming surfaces, induced rapid and transient expression of c-fos, c-jun, c-myc, and IL-6 mRNA. A second novel transcript for IL-6 was detected, but its significance remains unknown. Induction of all these messages was evident by 1 h; the levels of mRNA returned to baseline after 3-6 h. Concurrently, PTH had a small inhibitory effect on the expression of histone H4 mRNA. We conclude that, in vivo, PTH upregulates cell differentiation in trabecular bone by transient stimulation of the early response genes and IL-6, while downregulating cell proliferation.


Bone | 2000

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

D Stanislaus; X Yang; J.D Liang; J Wolfe; R.L Cain; J.E. Onyia; N Falla; P Marder; Joseph P. Bidwell; S.W Queener; Janet M. Hock

Osteoblast differentiation and function can be studied in situ in the metaphysis of growing long bones. Proliferation and apoptosis dominate in the primary spongiosa subjacent to the growth plate, and differentiation and function dominate in the proximal metaphysis. Apoptosis of osteocytes dominates at the termination of the trabeculae in diaphyseal marrow. As parathyroid hormone regulates all phases of osteoblast development, we studied the in vivo regulation by human parathyroid hormone (1-34) (PTH) of apoptosis in bone cells of the distal metaphysis of young male rats. Rats were given PTH at 80 microg/kg per day, once daily, for 1-28 days. Bone cells were defined for flow cytometry as PTH1-receptor-positive (PTH1R(+)) and growth factor-receptor-positive (GFR(+)) cells. Apoptotic cells stained positive for either TdT-mediated dUTP-X nick end labeling (TUNEL) or annexin V (annV(+)) were detected by either flow cytometry or immunohistochemistry. Apoptosis was also assessed at the tissue level by RNAse protection and caspase enzyme activity assays. PTH increased apoptotic osteoblasts in the proliferating zone and apoptotic osteocytes in the terminal trabecular zone, by 40%-60% within 2-6 days of PTH treatment, but values became equivalent to controls after 21-28 days of treatment. This transient increase was confirmed in PTH1R(+), GFR(+) bone cells isolated by flow cytometry. There was no detectable change in the steady-state mRNA levels of selected apoptotic genes. Starting at 3 days, at the tissue level, PTH inhibited activity of caspases, which recognize the DEVD peptide substrate (caspases 2, 3, and/or 7), but not those caspases recognizing LEHD or YVAD peptide sequences. We speculate that the localized and tissue level effects of PTH on apoptosis can be explained on the basis of its anabolic effect on bone. The transient increase in apoptosis in the proliferating zone and terminal trabecular zone may be the result of the increased activation frequency and bone turnover seen with daily PTH treatment. As once-daily PTH increases the number of differentiated osteoblasts, and as these and hematopoietic marrow cells dominate metaphyseal tissue, inhibition of caspase activity may contribute to their prolonged survival, enabling extension of trabecular bone into the diaphyseal marrow to increase bone mass.


Bone | 1997

Proliferating cells in the primary spongiosa express osteoblastic phenotype in vitro

J.E. Onyia; B. Miller; J. Hulman; J. Liang; Rachelle J. Sells Galvin; Charles A. Frolik; S. Chandrasekhar; A.K. Harvey; Joseph P. Bidwell; J. Herring; Janet M. Hock

We have shown that intermittent parathyroid hormone (PTH) treatment targets proliferating cells in the primary spongiosa of trabecular bone of young rats, resulting in an increased number of osteoblasts. To further characterize these proliferating osteoprogenitor cells, bromodeoxyuridine (BrdUrd) incorporated in vivo, was used as a marker to identify and isolate cells for in vitro studies. Proliferating cells were labeled in vivo in young rats with BrdUrd and 24 h later were isolated by trypsinization of sections of the primary spongiosa of the distal femur metaphysis. Within 12 h of isolation, BrdUrd+ cells formed distinct foci containing 20-500 cells with fibroblast morphology. Stimulation of proliferation as determined by [3H]-thymidine incorporation was observed for these cells in response to fetal bovine serum, platelet derived growth factor, and transforming growth factor beta-1. Neither insulin-like growth factor-1 (IGF-1) nor insulin stimulated proliferation PTH (1-34) and dexamethasone inhibited proliferation. The effects of PTH and dexamethasone were additive. Cells expressed the osteoblast phenotype as evidenced by synthesis of type I collagen, expression of high alkaline phosphatase activity, and production of increased intracellular cAMP in response to PTH (1-34). Confluent cell aggregates spontaneously formed mineralized nodules within 4-7 days, in the absence of inducers. These observations suggest that the primary spongiosa cells recapitulates the differentiation process in vitro in an accelerated fashion and may serve as a useful model to study osteoblast differentiation.


Journal of Cellular Biochemistry | 1997

Parathyroid hormone (1-34)–mediated interleukin-6 induction

Jude Onyia; Towia A. Libermann; Joseph P. Bidwell; D. Arnold; Yuan Tu; P. McClelland; Janet M. Hock

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin‐6 (IL‐6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL‐6 promoter fused (−1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast‐like osteosarcoma SaOS‐2 cells. We compared the effects of PTH on IL‐6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12‐myristate 13‐acetate (PMA), calcium ionophore A23187, interleukin‐1α (IL‐1α), prostaglandin E‐2 (PGE‐2), RS‐66271 (a parathyroid hormone–related peptide analog), and platelet‐derived growth factor‐BB (PDGF‐BB). Analyses of cell clones showed that IL‐6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001–100 nM) for 12 h stimulated CAT expression in a dose‐dependent manner (200–500% of control). Treatment with IL‐1α was more potent than PTH in inducing transcription of the IL‐6 promoter (900–1,000%). Activation of the cAMP‐PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS‐66271, previously shown to have PTH‐like effects, induced a comparable level of IL‐6 promoter expression. When examined together, PTH + RS‐66271 effects were comparable to PTH effects alone. Exposure to PGE‐2, PMA, PDGF‐BB, or A23187 for 12 h did not significantly alter IL‐6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS‐66271, and IL‐1α stimulate IL‐6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL‐6 expression. J. Cell. Biochem. 67:265–274, 1997.


Journal of Cellular Biochemistry | 1998

Analysis of differential gene expression in rat tibia after an osteogenic stimulus in vivo: Mechanical loading regulates osteopontin and myeloperoxidase

Rebecca R. Miles; Charles H. Turner; R. F. Santerre; Yuan Tu; Pam Mcclelland; Jeanne Argot; Bradley S. Dehoff; Christopher W. Mundy; Paul Robert Rosteck; Joseph P. Bidwell; James P. Sluka; Janet M. Hock; Jude Onyia

The skeleton has the ability to alter its mass, geometry, and strength in response to mechanical stress. In order to elucidate the molecular mechanisms underlying this phenomenon, differential display reverse transcriptase‐polymerase chain reaction (DDRT‐PCR) was used to analyze gene expression in endocortical bone of mature female rats. Female Sprague‐Dawley rats, approximately 8 months old, received either a sham or bending load using a four‐point loading apparatus on the right tibia. RNA was collected at 1 h and 24 h after load was applied, reverse‐transcribed into cDNA, and used in DDRT‐PCR. Parallel display of samples from sham and loaded bones on a sequencing gel showed several regulated bands. Further analysis of seven of these bands allowed us to isolate two genes that are regulated in response to a loading stimulus. Nucleotide analysis showed that one of the differentially expressed bands shares 99% sequence identity with rat osteopontin (OPN), a noncollagenous bone matrix protein. Northern blot analysis confirms that OPN mRNA expression is increased by nearly 4‐fold, at 6 h and 24 h after loading. The second band shares 90% homology with mouse myeloperoxidase (MPO), a bactericidal enzyme found primarily in neutrophils and monocytes. Semiquantitative PCR confirms that MPO expression is decreased 4‐ to 10‐fold, at 1 h and 24 h after loading. Tissue distribution analysis confirmed MPO expression in bone but not in other tissues examined. In vitro analysis showed that MPO expression was not detectable in total RNA from UMR 106 osteoblastic cells or in confluent primary cultures of osteoblasts derived from either rat primary spongiosa or diaphyseal marrow. Database analysis suggests that MPO is expressed by osteocytes. These findings reinforce the association of OPN expression to bone turnover and describes for the first time, decreased expression of MPO during load‐induced bone formation. These results suggest a role for both OPN and MPO expression in bone cell function. J. Cell. Biochem. 68:355–365, 1998.


Calcified Tissue International | 1995

Comparisons of In Vivo and In Vitro Models of the Response of Osteoblasts to Hormonal Regulation with Aging

Janet M. Hock; Jude E. Onyia; Joseph P. Bidwell

New in vitro models are needed to simulate the in vivo osteoblastic response to anabolic agents such as parathyroid hormone (PTH), and to more appropriately discriminate between aging and disease states in cells from older humans. Despite our detailed knowledge of the changes in vitro in bone forming cells with aging, the mechanisms and target cells by which aging modifies bone function in vivo or in vitro are still unknown. In vivo studies of aging in humans and rodents have shown that trabecular bone formation steadily declines with age in rats and humans, resulting in significant loss of bone mass [1-10]. Decreased bone formation may be due to a decrease in osteoblast proliferating precursors, to a decrease in the number of preosteoblasts that differentiate, or to decreased synthesis and secretion of essential matrix proteins. Histomorphometric analyses of the BMU (basic multicellular unit) in aging human bone correlated the reduction in wall thickness with age with the failure of osteoblasts to completely fill the resorption cavities during normal bone turnover [10]. This phenomenon was attributed to an age-related decline in osteoblast recruitment. In vitro models to study these effects of aging on bones have been developed by isolating stromal cells from bone marrow or bone cells from trabecular bone explants of aging rats and humans [8, 11-16]. Isolated cells were characterized as osteoblasts based on their proliferative and functional responses to calcium-regulating hormones, such as PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D3] and the constitutive expression of bone matrix proteins, such as osteocalcin, collagen I, and alkaline phosphatase. In humans aged a-60 years, a 50% decrease in proliferating bone cells was observed in humans aged a-30 years, but in humans aged 30-60 years, the proliferation rate of bone cells remained stable and similar [17]. In humans aged >60 years, anabolic growth factors such as insulin-like growth factor I (IGF-I) and transforming growth factor-B (TGF-f3), and hormones, such as PTH and calcitonin, increased DNA synthesis of bone cells by approximately 30% [13]. However, the dose required to stimulate this proliferation was approximately 10-fold higher than that required for


Critical Reviews in Eukaryotic Gene Expression | 2001

Involvement of the nuclear matrix in the control of skeletal genes: the NMP1 (YY1), NMP2 (Cbfa1), and NMP4 (Nmp4/CIZ) transcription factors.

Joseph P. Bidwell; Kitti Torrungruang; Marta B. Alvarez; Simon J. Rhodes; Rita Shah; Daniel R. Jones; Kanokwan Charoonpatrapong; Janet M. Hock; Andrew J. Watt


Journal of Biological Chemistry | 2002

DNA binding and gene activation properties of the Nmp4 nuclear matrix transcription factors.

Kitti Torrungruang; Marta B. Alvarez; Rita Shah; Jude Onyia; Simon J. Rhodes; Joseph P. Bidwell


Author | 2017

Megakaryocytes Enhance Mesenchymal Stromal Cells Proliferation and Inhibit Differentiation

Arbi M. Emmakah; Hussain E. Arman; Marta B. Alvarez; Paul Childress; Joseph P. Bidwell; William S. Goebel; Tien-Min Gabriel Chu; Melissa A. Kacena

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