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Copyright 2003 by Institute of Pharmacology EFFECTS OF DOXYCYCLINE ON DEVELOPMENTOF CHANGES IN HISTOMORPHOMETRIC PARAMETERS OFBONES INDUCED BY BILATERAL OVARIECTOMY IN RATS Joanna Folwarczna, Maria Pytlik, Waldemar Janiec Department of Pharmacology, Medical University of Silesia, Jagielloñska 4, PL 41-200 Sosnowiec, Poland Effects of doxycycline on development of changes in histomorphometric parameters of bones induced by bilateral ovariectomy in rats. J. FOLWAR-CZNA, M. PYTLIK, W. JANIEC. Pol. J. Pharmacol., 2003, 55, 433–441.
Tetracyclines are considered potential medication for the treatment of osteoporosis. The aim of the present study was to investigate the effects ofdoxycycline on development of unfavorable changes in bone histomor-phometric parameters induced by bilateral ovariectomy in rats. Doxycyclineat a dose of 20 mg/kg po daily was administered for 28 days to bilaterallyovariectomized and sham-operated 3-month-old Wistar rats. Bone histomor-phometric parameters of the tibia (transverse growth, width of periosteal andendosteal osteoid, area of the transverse cross-section of the diaphysis andarea of the transverse cross-section of the marrow cavity) and the femur(width of epiphyseal and metaphyseal trabeculae, width of epiphyseal carti-lage) were examined.
Bilateral ovariectomy caused symptoms of osteopenia in the rat bones.
Doxycycline counteracted the unfavorable changes in bone structure causedby estrogen deficiency. However, in the sham-operated rats doxycycline it-self induced deleterious effects in the trabecular bone.
Key words: doxycycline, ovariectomy, osteoporosis, rat
J. Folwarczna, M. Pytlik, W. Janiec INTRODUCTION
cline, IV. Ovariectomized group receiving doxycy-cline.
Doxycycline is a representative of broad-spec- Bilateral ovariectomy or sham-operation were trum tetracycline antibiotics, widely used both in performed under ether anesthesia. A longitudinal medical and dental practice. Numerous studies de- incision was made inferior to the rib cage on the monstrated that apart from their antimicrobial ac- dorsolateral body wall. The ovaries were exteri- tivity, tetracyclines exert pleiotropic effects on the orized, ligated and excised. Rats subjected to the host organism, leading to inhibition of connective sham surgical procedure had only the ovaries exte- tissue breakdown [14]. The most widely recog- nized of those effects is the ability of tetracyclines Treatment with doxycycline started three-four to inhibit matrix metalloproteinases (collagenases, days after the surgical procedure. Doxycycline (Doxy- gelatinases) [14]. Tetracyclines incorporate to bones cyclinum, Polfa, Poland) was administered daily by and influence bone remodeling. They were re- oral gavage for 4 weeks as doxycycline hydrochlo- ported to affect the function of osteoclasts [4, 31, ride at a dose equivalent to 20 mg/kg of doxycy- cline daily. The control groups received 0.9% sa- Tetracyclines are considered potential agents line in the same volume of 2 ml/kg po daily. The which could be applicable in the treatment of osteo- porosis [14]. Although there are also data indicating One day before the start and on the last day of disadvantageous effects of tetracyclines on bones administration of doxycycline or saline, the ani- [36, 39], the favorable effects of tetracyclines were mals were given tetracycline hydrochloride (20 described in experimental rickets [18], in osteope- mg/kg ip) in order to mark the calcification front.
nia in experimental streptozotocin-induced diabetes The next day, animals were sacrificed and the right [15, 32] and in prednisolone-induced osteopenia and left tibial and femoral bones and L-4 vertebra [13]. Minocycline and a chemically modified tetra- were prepared. In the isolated bones, mass and cycline (CMT-8) were reported to exert advanta- macrometric parameters were determined (length, geous effects in osteopenia induced by ovariectomy diameter of the diaphysis in the mid-length).
in rats [33, 43]. Doxycycline is more potent inhibi- In order to determine the content of mineral tor of collagenase than minocycline [14].
substances in bones, the L-4 vertebra, left tibia and Postmenopausal osteoporosis is the most com- femur were mineralized at the temperature of 620°C mon type of the bone loss. The main pathogenic factor of postmenopausal osteoporosis is a hormo- The right femoral and tibial bones were used to ne-dependent increase in bone resorption and ac- prepare histological specimens. From the tibial celerated loss of bone mass in the first 5–10 years bone, transverse cross-sections were made, perpen- after the menopause [26]. The model of bilaterally dicularly to the long axis, starting from the point ovariectomized rats mimics the changes occurring where fibula grows into it. From the femoral bone, in the skeletal system of postmenopausal women a longitudinal section of the distal epiphysis was due to estrogen deficiency [29, 44].
made, in the medial part, in the median plane. The The aim of the present study was to examine the sections were ground on the tarnished glass. The effects of doxycycline on the histomorphometric first preparation from the tibia remained unstained.
parameters of bones in rats with normal estrogen The rest of the preparations were stained using the level (sham-operated) and in rats with estrogen de- Tripp and MacKay method (without decalcifica- ficiency (bilaterally ovariectomized).
The histomorphometric measurements were made MATERIALS and METHODS
using a microscope Optiphot-2 (Nikon), connectedthrough RGB camera (Cohu) to personal computer The experiments were carried out on three- (program Lucia G 4.51, Laboratory Imaging), with month-old female Wistar rats, given distilled water final magnifications of 200 and 500 times.
to drink and fed a standard diet ad libitum. The ani- In the unstained preparation, the distance be- mals were divided into 4 groups (n = 5–8): I. Sham- tween the tetracycline stripes was measured, on the operated control group, II. Ovariectomized control periosteum side and on the marrow cavity side (pe- group, III. Sham-operated group receiving doxycy- riosteal and endosteal transverse growth).
DOXYCYCLINE, OVARIECTOMY AND BONE HISTOMORPHOMETRIC PARAMETERS In the stained preparation of the transverse Administration of doxycycline at a dose of 20 cross-section of the tibia, the width of the endosteal mg/kg po daily for 28 days to the sham-operated and periosteal osteoid was determined. In the longi- rats resulted in lesser body mass gain and smaller tudinal preparation from the femur, the width of mass of the thymus in comparison with the sham- epiphyseal cartilage and the width of trabeculae in operated control group. There were no statistically the epiphysis and metaphysis were measured.
significant changes in the examined parameters of The area of the transverse cross-section of the the skeletal system, with the exception of a de- cortical bone in the tibial diaphysis and the area of crease in the width of trabeculae in the femoral the transverse cross-section of the marrow cavity in epiphysis (by 10.4%, p < 0.05). The bone mineral the tibia were measured in the stained preparation, content to bone mass ratio for the L-4 vertebra was with the use of a lanameter (magnification 50 times).
reduced by 6%. The changes may indicate slight Results are presented as the mean ± SEM. Sta- disorders in bone remodeling caused by doxycy- tistical evaluation was performed using ANOVA cline. The width of epiphyseal cartilage was insig- and Student’s t-test for unpaired observations. When nificantly narrower than that of the sham-operated ANOVA revealed significant differences (p < 0.05), further analysis was performed using Student’s Administration of doxycycline at a dose of 20 t-test for unpaired observations.
mg/kg po daily for 28 days to the ovariectomizedrats did not statistically significantly affect thebody mass gain, mass of the uterus, mass of the thymus or the examined macrometric parameters ofbones in comparison with the ovariectomized con- Bilateral ovariectomy caused accelerated body trol group. Contrary to the ovariectomized control mass gain, a substantial decrease in the mass of the rats, in the doxycycline-treated group there were no uterus (by 75%) and an increase in the mass of the significant decreases in the bone mineral content to thymus (by 77%), as well as severe changes in the bone mass ratio in the examined bones in compari- skeletal system, in comparison with the group of son with the sham-operated control group. The ra- sham-operated control rats (Tab. 1). Significant de- tios were higher by 3.6%, 4.8% and 5.2% in the creases in the bone mineral content to bone mass tibia, femur and L-4 vertebra, respectively, than in ratios in the examined bones (by 6.5–9.9%) were the ovariectomized control group. In the tibia, the observed, indicating a decrease in bone mineral width of periosteal and endosteal osteoid in the doxycycline-treated ovariectomized rats statisti- Although macrometric parameters of the long cally significantly decreased (by 12.4% and 15%, bones did not significantly change (data not shown), respectively, p < 0.01) in comparison with the con- the loss of estrogen due to ovariectomy affected the trol group of ovariectomized rats. The transverse investigated histomorphometric parameters. In the cross section area of the marrow cavity and the ra- tibial bone, increases in the width of periosteal and tio of the transverse cross section area of the mar- endosteal osteoid (by 16%, p < 0.001, and 9.5%, re- row cavity to the transverse cross-section area of spectively) in comparison with sham-operated con- the diaphysis insignificantly decreased (by 8.3%), trol rats were observed, which, when confronted which may indicate the inhibition of the cortical with an increase in the periosteal transverse growth bone resorption. In the femur, the width of trabecu- by 10.6% (statistically insignificant), may indicate lae in the epiphysis and metaphysis increased by increased bone formation. An increase (by 7.4%) in 6.6% and 8.1%, respectively, in comparison with the transverse cross-section area of the marrow the ovariectomized control group. There was also cavity in the tibia may be the effect of the intensifi- an insignificant decrease in the width of epiphyseal cation of resorption processes in the cortical bone.
The width of trabeculae in the epiphysis and meta-physis of the femur decreased (by 18%, p < 0.01, DISCUSSION
and 9.8%, respectively) in comparison with thesham-operated control rats, indicating the accelera- Bilateral ovariectomy caused changes in the rat tion of bone resorption. The width of epiphyseal osseous system indicating the accelerated bone cartilage insignificantly increased.
loss, which were documented by the decreases in J. Folwarczna, M. Pytlik, W. Janiec Table 1. Effects of doxycycline (20 mg/kg po daily), administered for 4 weeks, on the histomorphometric parameters of bones in rats II – Ovariecto- III – Sham-opera- IV – Ovariectomi- ANOVA 370.41 ± 35.72 92.51 ± 6.73*** 388.87 ± 48.52 86.04 ± 6.66*** 364.90 ± 19.65 645.77 ± 74.29** 265.53 ± 43.85* 607.14 ± 50.70*** p < 0.001 cortical bone in the tibial diaphysis (mm ) Transverse cross-section area of the tibial 0.751 ± 0.066 Transverse cross-section area of the tibial 0.179 ± 0.011 Results are presented as means ± SEM (n = 5–8). ANOVA and then Student’s t-test for unpaired observations were used for estima- tion of statistical significance. NS – not significant in ANOVA. * significantly different (t-test) from the sham-operated control group (I); * p < 0.05, ** p < 0.01, *** p < 0.001. = significant difference (t-test) between the ovariectomized group treated with doxycycline (IV) and the ovariectomized control group (II); == p < 0.01 the ratios of bone mineral content to bone mass as increase in the transverse cross-section area of the well as the investigated histomorphometric para- marrow cavity in the tibia) was noted.
meters. In the cancellous bone (the trabeculae of The observed changes are consistent with nu- the femoral epiphysis and metaphysis), the intensi- merous previous reports [28, 37, 43]. Estrogen de- fication of bone resorption was observed. In the ficiency leads to the increased rate of bone remod- cortical bone, intensification of bone formation (an eling (both resorption and formation), because es- increase in the width of osteoid and transverse bone trogen decreases a number of remodeling cycles by growth) and intensification of bone resorption (an attenuating the birth rate of osteoclasts and osteo- DOXYCYCLINE, OVARIECTOMY AND BONE HISTOMORPHOMETRIC PARAMETERS blasts from their respective progenitors [25]. The inase activity in several rat models, including adju- imbalance between bone resorption and formation vant arthritis and periodontal disease [9].
in favor of the former observed in postmenopausal Tetracyclines also affect the structure and activi- osteoporosis is due to changes in the working life- ty of osteoclasts [30, 31, 33, 41]. The influence on span of osteoclasts and osteoblasts, as estrogen ex- osteoclasts includes decreasing the ruffled border erts pro-apoptotic effects on osteoclasts and anti- area of osteoclasts and inducing retraction of osteo- apoptotic effects on osteoblasts and osteocytes [25].
clasts, diminishing acid production and diminish- Recent data indicate that estrogen may exert an in- ing the secretion of lysosomal cysteine proteinases hibitory effect on resorption activity of mature os- (cathepsins), and inhibition of gelatinase activity teoclasts due to inhibition of organic matrix degra- [30, 31, 41]. From among proteolytic enzymes se- dation by cysteine proteinases [27].
creted by osteoclasts into an extracellular resorp- Administration of doxycycline at a dose of 20 tion lacuna, major roles in degradation of the or- mg/kg po daily for 4 weeks to the sham-operated ganic matrix (composed mainly of type I collagen) rats only slightly affected the investigated parame- have been suggested to be played by matrix metal- ters of the skeletal system. There were no changes loproteinases (particularly MMP-9 – gelatinase B) in the cortical bone, but the changes were observed and cysteine proteinases (particularly cathepsin K) in the cancellous bone (a decrease in the bone mine- [27]. Recent data suggest that organic matrix de- ral content/bone mass ratio in the L-4 vertebra and gradation by osteoclasts is initiated by matrix me- a decrease in the width of trabeculae in the femoral talloproteinases and continued by cysteine prote- epiphysis), which indicate predominance of bone inases [27]. Tetracyclines in vitro reduced the for- mation of mature osteoclasts and induced apoptosis The intensification of bone resorption demon- of osteoclasts [4]. In in vivo experiments carried strated in the present study is consistent with our out on rats, minocycline impaired osteoid tissue re- previous observation that doxycycline at a dose of moval as well as a number and resorbing activity of 100 mg/kg po daily, administered to normal control osteoclasts in a synchronized model of bone re- rats, intensified bone resorption in the cancellous modeling [22], and doxycycline suppressed surgi- and cortical bone [13]. Administration of oxytetra- cally induced recruitment of osteoclasts [19]. Doxy- cycline to young rats was reported to cause an inhi- cycline reduced alveolar bone loss occurring after bition of mineralization and possibly intensifica- periodontal surgery in rats and endodontal surgery in dogs [8]. Tetracyclines inhibited alveolar bone It should be emphasised that other reports de- loss in experimental periodontitis induced by Por- monstrated rather that tetracyclines caused inhibi- phyromonas gingivalis in rats [5]. Minocycline was tion of bone resorption. The inhibiting effect on reported to reduce bone resorption in ovariecto- bone resorption was demonstrated in vitro [6, 16, mized aged rats [43, 44]. Doxycycline (100 mg 17] and in vivo [14, 22, 33, 44]. Tetracyclines are daily for 3 months) decreased urinary excretion of inhibitors of matrix metalloproteinases, among oth- hydroxyproline (a bone resorption marker) in early ers collagenases [14]. Collagenase has been postu- lated to be involved in bone resorption [43]. Colla- The increase in the resorbing activity in rat genase, which is synthesized and secreted by osteo- bones observed in the present study may be the re- blasts in response to various hormones and factors, sult of the used model of the in vivo experiment on may degrade the barrier of non-calcified osteoid, rats with normal processes of bone remodeling. In allowing osteoclasts to reach the mineralized bone our abovementioned study [13], doxycycline at the surface lying below and start resorption of bone.
high dose of 100 mg/kg po daily also intensified The activity of collagenase may limit the rate of cortical bone formation, an effect not observed in bone resorption [30]. Several chemically modified the sham-operated rats in the present study. The tetracyclines that did not inhibit collagenase were dose used in the present study seems to be not high poor inhibitors of bone resorption [4]. Doxycycline enough to augment bone formation in rats with nor- is the most potent metalloproteinase inhibitor among antimicrobial tetracyclines [14]. The dose Administration of doxycycline (20 mg/kg po used in the present study (20 mg/kg po daily) was daily for 4 weeks) to the ovariectomized rats caused an effective dose inhibiting matrix metalloprote- an improvement in bone status in comparison with J. Folwarczna, M. Pytlik, W. Janiec the ovariectomized control group. Although in the However, the unfavorable effects of tetracy- present study doxycycline itself seemed to unfa- clines on the processes of bone formation were also vorably affect bone remodeling, it counteracted the described. For a long time it has been known that accelerated bone loss caused by ovariectomy, both tetracyclines exert disadvantageous side effects on in the trabecular (vertebra) and total (tibia and fe- the skeletal system, especially of children, leading mur) bones, normalizing the ratios of bone mineral to tooth discoloration and slowing of the longitudi- content to bone mass in the investigated bones.
nal growth of bones [36, 39]. Administration of Increases in the width of trabeculae in the femo- doxycycline to young rats reduced the longitudinal ral epiphysis and metaphysis, in comparison with bone growth [10] and the content of calcium and the ovariectomized control rats, may indicate inhi- phosphorus in bones [12]. Oxytetracycline caused bition of bone resorption or/and intensification of the inhibition of calcification of the epiphyseal car- bone formation in the cancellous bone. In the corti- tilage in young rats [24]. Long-term administration cal bone, the width of osteoid was significantly re- of tetracycline led to disorders of bone growth and duced. The thinning of the osteoid may indicate maturation in adult oophorectomized rhesus mon- either intensification of bone mineralization (im- keys [36]. Effect of doxycycline on collagen syn- provement in bone formation) or inhibition of bone thesis in other cells was different than in bones; matrix synthesis. As the transverse growth of the doxycycline inhibited collagen synthesis by bovine cortical bone in the tibia did not change in compari- articular chondrocytes cultured in alginate (type II son with the ovariectomized control group, the collagen) [3] and in cultured human skin fibro- former possibility seems to be more probable. Pro- cesses of bone resorption in the tibia from the side Estrogen prevents bone loss by blocking the of the marrow cavity seemed to be inhibited in production of proinflammatory cytokines in bone comparison with the ovariectomized control rats.
marrow and bone cells. After natural or surgically The inhibiting effect on bone resorption observed evoked menopause, the main consequence of the in the ovariectomized rats is consistent with many increased cytokine production in bones is an ex- abovementioned reports on tetracycline inhibition pansion of the osteoclastic pool due to the in- of bone resorption. The intensification of bone for- creased formation of osteoclasts and prolongation mation could also play a role in the beneficial effect of their life-span. Enhanced cytokine production of doxycycline on the bones of rats with estrogen leads also to the increased activity of mature osteo- clasts and increased osteoblastic activity. Among The intensifying effect of tetracyclines on bone the cytokines known to be regulated by estrogen formation was observed in different experimental are IL-1, IL-6, and TNFa [26]. Tetracyclines were models, especially in experimentally induced disor- reported to affect cytokine production. Tetracy- ders of bone remodeling, for example in osteopenia clines may protect rodents from lethal endotoxemia caused by streptozotocin-induced diabetes [2], and significantly reduce TNFa and IL-1 levels in prednisolone-induced osteopenia [13] and osteope- their serum [14]. Minocycline was reported to re- nia in ovariectomized aged rats [43].
duce the expression of IL-6 mRNA in bones of The favorable effects of tetracyclines in diabe- ovariectomized aged rats after marrow ablation tes-induced osteopenia were connected with im- [42], indicating that tetracyclines may prevent the provement of the impaired structure and function recruitment of osteoclasts by suppressing IL-6 pro- of osteoblasts, among others an increase in colla- duction by osteoblasts [29]. A chemically modified gen synthesis, which was demonstrated using ultra- tetracycline (CMT-8) reduced the IL-6 gene ex- structural cytochemical techniques and incorpora- pression in IL-1 stimulated MC3T3 murine osteo- tion of 3H-proline to osteoblasts and extracellular blastic cells in culture [29]. The effects on cytokine bone matrix [32, 34]. Minocycline increased the production may contribute to the mechanism of fa- expression of type I collagen mRNA in bones of vorable effect of doxycycline on bones of ovariec- ovariectomized aged rats after marrow ablation [42]. Tetracyclines also reversed the inhibitory ef- From among two major groups of proteolytic fect of periodontal infection on collagen synthesis enzymes secreted by osteoclasts suggested to par- (expression of type I and type XII collagen mRNAs ticipate in organic matrix degradation (matrix me- talloproteinases and cysteine proteinases), only the DOXYCYCLINE, OVARIECTOMY AND BONE HISTOMORPHOMETRIC PARAMETERS activity of cysteine proteinases is regulated by es- considered. US Food and Drug Administration ap- trogen [27]. As doxycycline in the present study proved the use of doxycycline in a subantimicro- did not inhibit bone resorption in the sham operated bial dose as an adjunct therapy in adult periodonti- rats, it is possible that inhibition of the excessive tis [14]. Long-term administration of doxycycline bone resorption observed in the ovariectomized in subantimicrobial dose (20 mg twice daily) in rats was due to inhibition of secretion of cysteine adult periodontitis did not result in detrimental shift proteinases, whose activity might have been in- in normal periodontal flora nor lead to the coloni- zation or overgrowth of periodontal or opportunis- The results of the present study indicating fa- tic pathogens [7]. It is not known if such dosage vorable effect of doxycycline on bones of ovariec- would be safe and effective to inhibit excessive tomized rats are consistent with the results obtained in ovariectomized aged rats treated with mino-cycline. Minocycline (about 22 mg/kg daily for8 weeks) caused substantial stimulation of bone REFERENCES
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Source: http://rabbit.if-pan.krakow.pl/pjp/pdf/2003/3_433.pdf

Policy code: 6145

Athletic Code School District Wauzeka-Steuben 2012-2013 2012-2013 (Changes/Updates/Reminders) • A student’s record for code violations goes into effect immediately upon signing this athletic code, no matter the grade level or age of the athlete and stays with them through high school. • Parents and athletes need to look over the policies and rules for athleti


Gemeindeseite vom 31. Oktober 2008 Gemeinde Sevelen Gemeinderatsverhandlungen vom 27. Oktober 2008 Direkt unter Gemeindewappen platzieren: Null-Stern-Hotel Eine zweite Probenacht findet vom Freitag, 14. November auf den Samstag, 15. November 2008 statt. Dieser Anlass wird vor al em für die Medien lanciert, welche für Berichterstattungen rund um die Welt besorgt sein werden.

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