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Biomedical subjects

D D Thompson

Publications and source records attributed to D D Thompson.

At least 19 recordsLinked to original sources
PubMed2006

Role of EP2 and EP4 receptor-selective agonists of prostaglandin E(2) in acute and chronic kidney failure.

We tested the efficacy of three selective agonists of prostaglandin E(2) (PGE(2)) receptor, EP2 (CP-536,745-01), EP2/4 (CP-043,305-02), and EP4 (CP-044,519-02), in two models of acute and chronic kidney failure. In the nephrotoxic mercury chloride (HgCl(2)) rat model of acute kidney failure systemically administered EP4 agonist reduced the serum creatinine values and increased the survival rate. Although the EP2 or the EP2/4 agonist did not change the serum creatinine values, the EP2 receptor agonist increased the survival rate. Histological evaluation of kidneys from EP4-treated rats indicated less proximal tubular necrosis and less apoptotic cells. In a rat model of chronic renal failure, the three receptor agonists decreased the serum creatinine and increased the glomerular filtration rate at 9 weeks following therapy. Kidneys treated with the EP4 agonist had less glomerular sclerosis, better preservation of proximal and distal tubules and blood vessels, increased convoluted epithelium proliferation and less apoptotic cells. Nephrectomy had no influence on the expression of the EP4 receptor, whereas EP2 receptor expression was reduced by 50% and then corrected following treatment with EP2 and EP2/4 receptor agonists. These findings suggest that PGE(2) has an important role in acute kidney failure via the EP4 receptor, whereas in chronic kidney failure both EP2 and EP4 receptors are equally important in preserving the progression of chronic kidney failure. Thus, agonism of EP2 and EP4 receptors may provide a basis for treating acute and chronic kidney failure.

Acute Kidney Injury↗
PubMed2005

Osteopenia and impaired fracture healing in aged EP4 receptor knockout mice.

The EP4 receptor, one of the subtypes of the prostaglandin E2 (PGE2) receptor, plays a critical role in the anabolic effects of PGE2 on bone. However, its role in the maintenance of bone mass in aged animals and its role in fracture healing is not well known. Our studies addressed these issues by characterizing the skeletal phenotype of aged, EP4 receptor knockout (KO) mice, and by comparing fracture healing in aged KO mice versus wild type (WT) mice. There was no significant difference in body weight and femoral length between KO and WT mice at 15 to 16 months of age. Lower bone mass was seen radiographically in both axial and long bones of KO mice relative to WT mice. Micro-CT images of the distal femurs showed thinner cortices, fewer trabeculae, and a deteriorated trabecular network in KO mice. Total bone content, trabecular content, and cortical content, as assessed by pQCT in the distal femur, were lower in KO mice than WT controls. Histomorphometric measurements showed that trabecular bone volume and bone formation rate were significantly decreased whereas osteoclast number on trabecular surface and eroded surface on endocortical surface were significantly increased in KO mice. These data indicated that deleting the EP4 receptor resulted in an imbalance in bone resorption over formation, leading to a negative bone balance. The lower bone formation rate in EP4 KO mice was primarily due to decreased mineralizing surface, suggesting that the defect in overall bone formation was mainly due to the defect in osteoblastogenesis. Fracture healing was examined in KO and WT mice subjected to a transverse femoral fracture. Callus formation was significantly delayed as evidenced both radiographically and histologically in the fractured femurs of KO mice compared with those of WT mice. KO mice had significant decreases in total callus area, cartilaginous callus area, and bony callus area 2 weeks after fracture. By 4 weeks, complete bony bridging was seen in WT mice but not in KO mice. These data demonstrate that the absence of the EP4 receptor decreases bone mass and impairs fracture healing in aged male mice. Our findings indicate that the EP4 receptor is a positive regulator in the maintenance of bone mass and fracture healing.

Aging↗
PubMed2004

Alfacalcidol prevents age-related bone loss and causes an atypical pattern of bone formation in aged male rats.

The current study was designed to investigate the skeletal effects of alfacalcidol in aged rats. Eighteen-month-old male rats were treated with 0, 0.1, or 0.2 microg/kg/d of alfacalcidol by daily oral gavage, 5 days/week for 12 weeks. At the beginning of the treatments, one group of rats was euthanized to serve as a baseline control. At the end of the study, the second lumbar vertebrae and the right tibial diaphysess were processed for bone histomorphometric analysis. The fourth lumbar vertebrae were subjected to strength testing. The control group of rats at 21 months of age had decreased serum testosterone levels and decreased cancellous bone mass associated with increased bone turnover on the trabecular surface. The older rats had increased bone turnover on the endocortical surface and decreased bone formation on the periosteal surface compared with the 18-month group. In contrast, alfacalcidol treatment increased cancellous and cortical bone mass in aged male rats. Trabecular bone resorption was decreased whereas bone formation was maintained or increased in the rats treated with alfacalcidol. In addition, endocortical bone formation was decreased whereas periosteal bone formation was increased in the rats treated with alfacalcidol compared with vehicle-treated rats. Marrow trabecular bone area was increased by alfacalcidol treatment in tibial diaphyses. Furthermore, bone strength of the lumbar vertebral body was increased after alfacalcidol treatment. An atypical pattern of bone formation on endosteal bone surfaces was seen in the rats treated with alfacalcidol. The atypical bone formation is characterized by small, focal packets of newly formed bone on trabecular and endocortical bone surfaces. This gave the appearance of the formation of "bone buds" emanating from trabecular surfaces. These bony outgrowths were mineralized and demonstrated significant fluorochrome label indicating recent mineralization. Also, lamellae of the bony buds did not run parallel to those of the trabecular plate to which they are attached. Arrest lines presented in most of the "bone buds". In summary, alfacalcidol treatment increased cancellous and cortical bone mass and improved bone strength, resulting in the prevention of age-related bone loss in aged male rats. An atypical pattern of bone formation observed in this study may be a result of minimodeling based bone formation stimulated by alfacalcidol treatment.

Aging↗
PubMed2003

An EP2 receptor-selective prostaglandin E2 agonist induces bone healing.

The morbidity and mortality associated with impaired/delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E2 (PGE2) causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton. However, due to side effects, PGE2 is an unacceptable therapeutic option for fracture healing. PGE2 mediates its tissue-specific pharmacological activity via four different G protein-coupled receptor subtypes, EP1, -2, -3, and -4. The anabolic action of PGE2 in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and/or EP4 receptor subtypes in bone formation. We identified an EP2 selective agonist, CP-533,536, which has the ability to heal canine long bone segmental and fracture model defects without the objectionable side effects of PGE2, suggesting that the EP2 receptor subtype is a major contributor to PGE2's local bone anabolic activity. The potent bone anabolic activity of CP-533,536 offers a therapeutic alternative for the treatment of fractures and bone defects in patients.

Animals↗
PubMed2003

Alfacalcidol restores cancellous bone in ovariectomized rats.

Active vitamin D metabolites have been demonstrated to reduce vertebral and hip fractures in elderly patients. A number of in vitro and in vivo pre-clinical studies have suggested that vitamin D may effectively stimulate osteoblastic activity and exert an anabolic effect on bone. The current study was designed to further explore the ability of an active vitamin D analog to restore bone in a skeletal site with established osteopenia in ovariectomized (OVX) rats. Female Sprague Dawley rats at five months of age and 8 weeks after sham ovariectomy or ovariectomy were randomly divided into 7 groups with 10 per group. At the beginning of the treatments, one group of sham-operated rats and one group of OVX rats were sacrificed to serve as baseline controls. Another group of sham-operated rats and one group of OVX rats were treated with vehicle for 4 weeks. The OVX rats in the remaining groups were treated with alfacalcidol at 0.05, 0.1 or 0.2 microg/kg/d by daily oral gavage, 5 days/week for 4 weeks. As expected, estrogen depletion caused high bone turnover and cancellous bone loss in lumbar vertebra of OVX rats. Alfacalcidol treatment at 0.1 or 0.2 but not 0.05 microg/kg/d increased serum calcium and phosphorus in OVX rats as compared with vehicle treatment. In addition, serum parathyroid hormone was suppressed, whereas serum osteocalcin was increased by alfacalcidol at all dose levels. Furthermore, histomorphometric data of 2nd lumbar vertebral body revealed that cancellous bone volume in OVX rats treated with alfacalcidol at 0.1 or 0.2 microg/kg/d was increased to the level of sham-operated rats treated with vehicle. This increment in cancellous bone mass was accompanied by increases in trabecular number and thickness and a decrease in trabecular separation. Moreover, osteoclast surface and number were significantly decreased, whereas bone formation variables such as mineralizing surface and bone formation rate were significantly increased in alfacalcidol- treated OVX rats compared with those of vehicle-treated OVX rats. Finally, a linear regression analysis showed that alfacalcidol treatment dose-dependently altered most of the variables measured in the current study. In conclusion, alfacalcidol completely restores cancellous bone by stimulating bone formation and suppressing bone resorption in lumbar vertebra of OVX rats when the treatment is started at an early phase of osteopenia. The evidence of increased bone formation by alfacalcidol treatments further supports the notion that active vitamin D metabolites or their analogs may exert anabolic effects on bone.

Journal Article↗
PubMed2003

Regulation of osteoclast differentiation by statins.

HMG-CoA reductase inhibitor (statin) treatment is frontline therapy for lowering plasma cholesterol levels in patients with hyperlipidemia. In a few case studies, analysis of clinical data has revealed a decreased risk of fracture in patients on statin therapy. However, this reduction in the incidence of fracture is not always observed nor is it supported by an increase in bone density, which further complicates our understanding of the role of statins in bone metabolism. Thus, the precise role of statins in bone metabolism remains poorly understood. In this study, we examined the effect of statin treatment on osteoclastogenesis. Treatment with lovastatin resulted in a significant, dose-dependent decrease in the numbers of differentiated osteoclasts and decreased cholesterol biosynthesis activity with an EC(50) similar to that observed in freshly isolated rat or cultured human liver cells. Studies assessing the role of mevalonate metabolites in the development of the osteoclasts demonstrated that geranylgeraniol, but not squalene or farnesol was important for the development and differentiation of osteoclasts, implicating protein geranylgeranylation rather than protein farnesylation as a key factor in the osteoclast differentiation process. In conclusion, our data indicate that lovastatin inhibits osteoclast development through inhibition of geranylgeranylation of key prenylated proteins and that the bone effects of statins are at least partially due to their effects on osteoclast numbers.

Journal Article↗
PubMed2002

Regulation of BMP-7 expression by retinoic acid and prostaglandin E(2).

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) gene superfamily of growth and differentiation factors. Members of the BMP family were originally cloned and characterized by their ability to induce ectopic bone formation. Of the various BMPs cloned, the bone inductive ability of BMP-7 (OP-1) and BMP-2 has been well characterized. Both BMP-7 and -2 have been shown to have clinical utility in the healing of non-union fractures. However, in spite of the various advances in BMP research, the physiological regulation of BMPs is not well understood. Here we studied the expression of BMP-7 by cloning a 4.6-kB fragment of the human BMP-7 promoter (hBMP-7p) and placing it upstream of a luciferase reporter. The promoter reporter construct was stably transfected into different cell backgrounds and its regulation by various factors was investigated. We show that retinoic acid (RA) treatment results in an upregulation of the hBMP-7p reporter activity. This regulation of the hBMP-7p was further confirmed by Northern blot, PCR, and Western blot analyses, which showed an increase in both BMP-7 mRNA and protein expression upon treatment with RA. We further show that RA specifically upregulates expression of osteocalcin via activation of BMP-7 mRNA and protein in vitro. Similarly, prostaglandin E(2) (PGE(2)) treatment increases BMP-7 mRNA and protein levels, but does not transcriptionally activate the hBMP-7p. Additionally, in vivo expression of BMP-7 in bone was increased upon PGE(2) treatment. In conclusion, RA and PGE(2) upregulate BMP-7 protein expression both in vitro and in vivo.

Base Sequence↗
PubMed2002

The role of estrogen receptor-beta, in the early age-related bone gain and later age-related bone loss in female mice.

The molecular and cellular mechanism of estrogen action in skeletal tissue remains unclear. The purpose of this study was to understand the role of estrogen receptor-beta, (ERbeta) on cortical and cancellous bone during growth and aging by comparing the bone phenotype of 6- and 13-month-old female mice with or without ERbeta. Groups of 11-14 wild-type (WT) controls and ERbeta knockout (BERKO) female mice were necropsied at 6 and 13 months of age. At both ages, BERKO mice did not differ significantly from WT controls in uterine weight and uterine epithelial thickness, indicating that ERbeta does not regulate the growth of uterine tissue. Femoral length increased significantly by 5.5% at 6 months of age in BERKO mice compared with WT controls. At 6 months of age, peripheral quantitative computerized tomography (pQCT) analysis of the distal femoral metaphysis (DFM) and femoral shafts showed that BERKO mice had significantly higher cortical bone content and periosteal circumference as compared with WT controls at both sites. In contrast to the findings in cortical bone, at 6 months of age, there was no difference between BERKO and WT mice in trabecular density, trabecular bone volume (TBV), or formation and resorption indices at the DFM. In 13-month-old WT mice, TBV (-41%), trabecular density (-27%) and cortical thickness decreased significantly. while marrow cavity and endocortical circumference increased significantly compared with 6-month-old WT mice. These age-related decreases in cancellous and endocortical bone did not occur in BERKO mice. At 13 months of age, BERKO mice had significantly higher total, trabecular and cortical bone, while having significantly lower bone resorption, bone formation and bone turnover in DFM compared with WT mice. These results indicate that deleting ERbeta protected against age-related bone loss in both the cancellous and endocortical compartments by decreasing bone resorption and bone turnover in aged female mice. These data demonstrate that in female mice, ERbeta plays a role in inhibiting periosteal bone formation, longitudinal and radial bone growth during the growth period, while it plays a role in stimulating bone resorption, bone turnover and bone loss on cancellous and endocortical bone surfaces during the aging process.

Journal Article↗
PubMed2001

Prospective randomized trial of azathioprine in cryopreserved valved allografts in children.

BACKGROUND: The purpose of this study was to prospectively assess the effects of azathioprine on the humoral immune response to HLA alloantigens and allograft function in children receiving cryopreserved valved allografts. METHODS: We randomized 13 children to receive azathioprine or not to receive azathioprine (controls) after receiving a cryopreserved valved allograft. Azathioprine patients received intraoperatively 4 mg/kg of azathioprine and 2.0 +/- 0.5 mg/kg once daily for 3 months after operation. Panel reactive antibodies against HLA class I and class II alloantigens were measured before, 1 month, and 3 months after operation. RESULTS: Panel reactive antibodies were not significantly different between the azathioprine and control groups before (0.0% +/- 0% versus 1.6% +/- 1%), 1 month (59% +/- 17% versus 71% +/- 12%), or 3 months (84% +/- 15% versus 96% +/- 1.3%) after operation. There were no differences in degree of allograft valve stenosis between azathioprine (31.5 +/- 26 mm Hg, 13.4 +/- 7 months postoperatively) and control groups (25.4 +/- 11 mm Hg, 17.2 +/- 10 months postoperatively) or allograft valve insufficiency. CONCLUSIONS: Azathioprine does not significantly decrease the immune response to HLA alloantigens or affect the function of cryopreserved valved allografts used in children to repair congenital heart defects.

Adolescent↗
PubMed2001

Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats.

The purpose of this study was to evaluate if long-term (6 months) treatment with lasofoxifene (LAS), a new selective estrogen receptor modulator (SERM), can protect against age-related changes in bone mass and bone strength in intact aged male rats. Sprague-Dawley male rats at 15 months of age were treated (daily oral gavage) with either vehicle (n = 12) or LAS at 0.01 mg/kg per day (n = 12) or 0.1 mg/kg per day (n = 11) for 6 months. A group of 15 rats was necropsied at 15 months of age and served as basal controls. No significant change was found in body weight between basal and vehicle controls. However, an age-related increase in fat body mass (+42%) and decrease in lean body mass (-8.5%) was observed in controls. Compared with vehicle controls, LAS at both doses significantly decreased body weight and fat body mass but did not affect lean body mass. No significant difference was found in prostate wet weight among all groups. Total serum cholesterol was significantly decreased in all LAS-treated rats compared with both the basal and the vehicle controls. Both doses of LAS treatment completely prevented the age-related increase in serum osteocalcin. Peripheral quantitative computerized tomography (pQCT) analysis at the distal femoral metaphysis indicated that the age-related decrease in total density, trabecular density, and cortical thickness was completely prevented by treatment with LAS at 0.01 mg/kg per day or 0.1 mg/kg per day. Histomorphometric analysis of proximal tibial cancellous bone showed an age-related decrease in trabecular bone volume (TBV; -46%), trabecular number (Tb.N), wall thickness (W.Th), mineral apposition rate, and bone formation rate-tissue area referent. Moreover, an age-related increase in trabecular separation (Tb.Sp) and eroded surface was observed. LAS at 0.01 mg/kg per day or 0.1 mg/kg per day completely prevented these age-related changes in bone mass, bone structure, and bone turnover. Similarly, the age-related decrease in TBV and trabecular thickness (Tb.Th) and the age-related increase in osteoclast number (Oc.N) and osteoclast surface (Oc.S) in the third lumbar vertebral cancellous bone were completely prevented by treatment with LAS at both doses. Further, LAS at both doses completely prevented the age-related decrease in ultimate strength (-47%) and stiffness (-37%) of the fifth lumbar vertebral body. These results show that treatment with LAS for 6 months in male rats completely prevents the age-related decreases in bone mass and bone strength by inhibiting the increased bone resorption and bone turnover associated with aging. Further, LAS reduced total serum cholesterol and did not affect the prostate weight in these rats. Our data support the potential use of a SERM for protecting against the age-related changes in bone and serum cholesterol in elderly men.

Adipose Tissue↗
PubMed2001

Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.

Administration, Oral↗
PubMed2001

A comparison of the anabolic effects of rat and bovine parathyroid hormone (1-34) in ovariectomized rats.

The current study was designed to compare the skeletal effects of comparable doses of rat parathyroid hormone 1-34 (rPTH) and bovine parathyroid hormone 1-34 (bPTH) in ovariectomized (OVX) rats. Female Sprague-Dawley rats were OVX or sham-operated at 6 months of age and maintained untreated for 28 days after surgery. Baseline control and OVX rats were sacrificed at the beginning of treatment. Beginning 28 days post-OVX, the remaining rats were subcutaneously injected daily with rPTH or bPTH at 0, 5, 25, or 50 microg/kg/d for 28 days. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of the distal femoral metaphyses were determined ex vivo using dual energy X-ray absorptiometry. Quantitative bone histomorphometry was performed on undecalcified longitudinal sections of the proximal tibia from each rat. Baseline OVX rats exhibited osteopenia as demonstrated by their significantly reduced femoral BMD and proximal tibia cancellous bone volume compared with those of baseline sham controls. Both rPTH and bPTH restored bone in OVX rats by markedly stimulating bone formation in a dose-dependent manner. However, a difference in potency between the two forms of PTH was evident. The percentage increases of BMC, BMD, cancellous bone volume, trabecular thickness, mineralizing surface, and bone formation rate in the OVX rats treated with bPTH at 5 microg/kg/d were the same as or above those treated with rPTH at the 25 microg/kg/d dose level. A relative potency analysis showed that bPTH was approximately 4- to 6-fold relatively more potent than rPTH in increasing distal femoral BMD as well as cancellous bone volume, mineralizing surface, and bone formation rate of proximal tibial metaphyses at comparable dose levels and a given time. These results may serve as a reference for in vivo study design when rPTH or bPTH are to be the agents for studies on bone anabolism.

Journal Article↗
PubMed2001

Long-term effects of aging and orchidectomy on bone and body composition in rapidly growing male rats.

The purpose of this study was to assess the long-term effects of aging and sex hormone deficiency on skeletal metabolism and body composition in rapidly growing male rats. Sprague-Dawley male rats were sham-operated (sham) or orchidectomized (ORX) at 3 months of age. Eight sham rats and eight ORX rats at each time point were serially sacrificed at 3, 4, 8, 12, 15, and 23 months of age. Bone mass in sham rats rapidly increased until 8 months of age, then slightly increased between 8 to 12 months of age; thereafter, an age-related decrease in bone mass was found between 12 to 23 months of age. In sham rats, bone formation parameters decreased between 3 and 8 months, and maintained at the lower level between 8 and 23 months of age, while bone resorption parameters decreased between 3 and 12 months, and thereafter, increased with age between 12 and 23 months of age. ORX significantly inhibited age-related gain in body weight, lean body mass, and cancellous and cortical bone mass and decreased peak bone mass (approximately 20% less versus sham). Further, we found that the lower bone and lean body mass in ORX rats was due to the lack of age-related gain rather than the net loss from basal controls. These data suggest that sex hormones are important factors for the accumulation of peak bone and lean body mass in male rats.

Journal Article↗
PubMed2000

Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat.

It has been well documented that selective estrogen receptor modulators (SERMs) can prevent bone loss in ovariectomized rats and postmenopausal women. The purposes of this study were to determine the effects of a potent and orally active SERM, lasofoxifene (CP-336,156), on bone mass, bone strength, total serum cholesterol, prostate weight, and histology in adult male orchidectomized (ORX) rats. Sprague Dawley male rats at 10 months of age were divided into 6 groups, with 10 rats/group. The first group was necropsied on day 0 and served as basal controls. The remaining rats were either sham operated (n = 10) and treated orally with vehicle, or ORX (n = 40) and treated with either vehicle or lasofoxifene at 1, 10, or 100 microg/kg x day for 60 days. Total serum cholesterol, prostate weight and histology, distal femoral bone mineral density (DFBMD) by dual energy x-ray absorptiometry, and static and dynamic bone histomorphometry of the third lumbar vertebral body were determined. Maximal load and stiffness of the fifth lumbar vertebral body were also determined by compression tests. Age-related decreases in DFBMD (-9%) and trabecular bone volume (TBV; -13%) of the third lumbar vertebral body were found in sham-operated rats compared with basal controls. ORX induced significant increases in total serum cholesterol (+31%), eroded surface (+48%), activation frequency of bone turnover (+103%) and significant decreases in prostate weight (-89%), DFBMD (-14%), TBV (-23%), and maximal load (-17%) compared with basal controls. Compared with sham controls, ORX induced significant increases in eroded perimeter and activation frequency. Lasofoxifene decreased body weight in all dose groups compared with both sham and ORX control values. Compared with ORX controls, ORX rats treated with lasofoxifene at 10 or 100 microg/kg x day had significantly lower percent eroded perimeter activation frequency and significantly higher DFBMD, TBV, and maximal load. Further, lasofoxifene at 10 and 100 microg/kg x day significantly decreased total serum cholesterol by 46% and 68% in ORX rats, whereas no effect was found in prostate weight and histology parameters compared with ORX control values. These data showed that lasofoxifene prevented bone loss by inhibiting bone turnover associated with aging and orchidectomy in 10-month-old male rats. Further, lasofoxifene decreased total serum cholesterol and did not affect the prostate in these rats. These results suggest that SERMs such as lasofoxifene may be useful therapeutic agents for preventing bone loss in elderly men with some degree of hypogonadism.

Aging↗
PubMed1999

Droloxifene does not blunt bone anabolic effects of prostaglandin E2, but maintains prostaglandin E2-restored bone in aged, ovariectomized rats.

Droloxifene (DRO) is a selective estrogen receptor modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2 (PGE2)-restored bone after discontinuation of PGE2 in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2 plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2 (3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2 plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2 or PGE2 plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (-15%, -19%, and -19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2 alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2 alone or PGE2 plus DRO. Upon cessation of PGE2 treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (-12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2 plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2 alone or both PGE2 and DRO. However, treatment with DRO following 2 months of PGE2 plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2 in PGE2 alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibited bone turnover and prevented bone loss induced by withdrawal of PGE2. Trabecular bone mass was maintained in the PGE2 plus DRO followed by vehicle group and further increased in the PGE2 plus DRO followed by DRO groups. We found that: (a) DRO is efficacious in maintaining PGE2-restored bone after discontinuation of PGE2; (b) DRO did not blunt the anabolic effects of PGE2; (c) bone loss occurred after cessation of treatment in the PGE2-alone group, whereas it was maintained after cessation of treatment in PGE2 plus DRO group; and (d) an additional anabolic effect was found in ovx rats treated with PGE2 plus DRO followed by DRO.

Absorptiometry, Photon↗
PubMed1998

Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family.

Members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors have been identified in a wide variety of organisms, ranging from invertebrates to mammals. Bone morphogenetic proteins (BMPs) constitute a subgroup of proteins belonging to the TGF-beta superfamily. BMPs were initially identified by their ability to induce endochondral bone formation at ectopic sites, suggesting a critical role for this family in development and regeneration of the skeleton. They are also expressed at a variety of nonskeletal sites during development, suggesting possible extraskeletal roles for these proteins. We cloned a novel member of the BMP family that is expressed at high levels in the placenta and the prostate and that we have designated as prostate-derived factor (PDF). Based on cDNA sequence analysis, the predicted PDF protein contains two cysteines in addition to the seven conserved cysteines that are the hallmark of the members of the TGF-beta superfamily. In addition, Northern blot hybridization to poly(A)+ RNA showed low levels of expression in the kidney and pancreas. We further characterized the expression of this member of the BMP family by in situ hybridization and immunohistochemistry. These results show high expression in the terminal villae of the placenta. The expression of the protein as visualized by immunohistochemistry shows an expression pattern identical to that of the message in the terminal villae of the placenta. In day 18 rat embryos, protein expression was also seen in the skin and in the cartilaginous tissue of developing skeleton. Orchidectomy and dihydrotestosterone treatment of rats revealed that PDF expression is regulated by androgens in the prostate. In addition, subcutaneous implantation of recombinant PDF induced cartilage formation and the early stages of endochondral bone formation. These data indicate that PDF has a functional relationship to the BMPs.

Amino Acid Sequence↗