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PGE2 stimulates both resorption and formation of bone in vitroDifferential responses of the periosteum and the endosteum in fetal rat long bone cultures.

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PGE2 Stimulates Both Resorption and Formation of
Bone In Vitro: Differential Responses of the
Periosteum and the Endosteum in Fetal Rat Long
Bone Cultures
Yale University School of Medicine, Departments of Cell Biology and Internal Medicine, New
Haven, CT 06510
The ability of PGE2 to stimulate bone resorption in vitro and in
vivo is well established but the effects of this compound on bone formation are still
controversial. Recent clinical reports have suggested that long-term infusion of PGE
in infants with cyanotic heart diseases led to a stimulation of periosteal bone
formation and to hyperostosis.
M) in bone organ
In the present report, we describe the effects of PGE2
cultures on bone resorption, measured by the release of 45Calcium and the number
of osteoclasts in sections of cultured bones, and bone volume, by measuring separately medullary and cortical areas. PGE2 induced a marked increase in 45Ca release
and in cortical and medullary osteoclast numbers over 4 days in vitro; despite this
increase in bone resorption, cortical bone volume remained constant, indicating a
parallel increase in bone resorption and formation a t this site. Morphological and
quantitative data demonstrated a higher extent of osteoblastic surface along the
periosteum of PGE2-treated bones when compared with control cultures. Medullary
bone volume, on the other hand, decreased sharply during the culture period,
demonstrating a lack of parallel increase in bone formation at this site.
It is concluded that, under these experimental conditions, prostaglandin E2 stimulated both resorption and formation along the periosteum and only bone resorption
along the endosteum of the cultured bones. The overall effect of PGE2 on bone a s a
whole, however, was net bone loss.
During bone remodeling, bone resorption and bone
formation normally occur as two successive steps of the
same sequence of events (Frost, 1964; Baron, 1977).
Nevertheless, studies on the effects of prostaglandins
(PG) on bone have usually considered separately the
changes in bone resorption and in bone formation both
in vitro (Klein and Raisz, 1970; Dietrich et al., 1975;
Holtrop and Raisz, 1979) and in vivo (Santoro et al.,
1977; Goodson et al., 1974; Tashjian et al., 1972).
The effects of PG of the E series on bone resorption are
rather well characterized: in vitro a s well as in vivo
after administration of PGE or in various pathological
conditions (Powles et al., 1973; Seyberth et a1.,1975;
Eilon and Mundy, 1978; Tashjian et al., 1972; Franklin
and Tashjian, 1975; Voelkel et al., 19751, PGE have been
shown to increase bone resorption through a n increase
in the number of osteoclasts (Rifkin et al., 1980)and/or
in their activity (Holtrop and Raisz, 1979).
More controversial are the effects of PGE on bone
formation. It was suggested (Raisz and Koolemans-Beynen, 1974) that in vitro they inhibited bone formation as
measured by the incorporation of labeled proline into
bone matrix. Similarly, both a n increase in resorption
and a decrease in formation were reported in rabbits
bearing the prostaglandin-producing VX2 carcinoma
(Wolfe et al., 1978) and in rats injected daily for up to 9
0 1985 ALAN R. LISS, INC.
days with PGE (Yonaga and Morimoto, 1979). On the
other hand, a n opposite effect on bone formation has
been suggested by some experimental and clinical studies (Blumenkrantz and Sondergard, 1972; Ueda et al.,
1980; Ringel et al., 1982). Similarly, the results of Vanderwiel and Talmage (1979) have suggested a n increase
in calcium flow to the bone under PGE2 infusion.
The present study was therefore undertaken to evaluate in a single culture system (Raisz and Niemann,
1969; Nefussi et al., 1982) the effects of PGE2 on both
bone volume and bone resorption using a concentration
(lop5M ) l that was shown in previous studies to induce
maximum stimulation of bone resorption and inhibition
of collagen synthesis (Klein and Raisz, 1970; Raisz and
Koolemans-Beynen, 1974). Owing to the fact that histo-
Received October 17, 1983; accepted August 6,1984.
Jean-Raphael Nefussi's present address is University of Paris 7,
Paris, France.
Address reprint request to Dr. Roland Baron, Endocrine Section,
Department of Internal Medicine, Yale University School of Medicine,
333 Cedar Street, New Haven, CT 06510.
'A typographical error was present in a previously published abstract of part of this work (Calcif. Tissue Int. 33:298, 1981)mentioning
erroneously a concentration of
M PGE2. It should have been
morphometric methods allow a distinction between different areas of the explants which might react differently
to the same stimulus, the results demonstrate that 1)
bone resorption is stimulated by PGE2 through a n increase in the number of osteoclasts; 2) the amount of the
bone present in the cortical bone, however, remains constant despite the increase in resorption and in 45Ca
release, indirectly implying that, a t this concentration,
bone formation is also stimulated along the periosteum,
as confirmed by a measured increase in osteoblastic
surface; and 3) medullary bone resorption is rapid and
results in a n overall net bone loss.
Bone Culture System
Following the technique of Raisz and Niemann (1969)
for bone cultures, three Sprague-Dawley rats were injected on the 18th day of pregnancy with 500 pCi of
45CaC1z (specific activity - 30 Ci/gm; New England Nuclear, Boston, MA). One day later, the rats were sacrificed and the fetal radii and ulnae were dissected out.
The cartilage ends were removed and the remaining
midshafts were individually cultured in a 24-well culture dish with modified BGJb medium (Gibco, Grand
Island, NY) supplemented with ascorbic acid (0.1 mg/ml;
Fischer Sci. Co.), streptomycin (50 pg/ml; Gibco), penicillin (50 units/ml; Gibco) bovine serum albumin (1mgiml,
Fraction V; Sigma, St. Louis, MO) and L-glutamine (2 x
lop3 M, Gibco). The dishes were placed in a humidified
incubator a t 37°C in a n atmosphere of 5% COz and air.
The bones were precultured from the first day either
in supplemented BGJb medium or in the same medium
but containing
M PGE2 for the experimental bones.
After a change in medium, the bones were kept in culture for 4 additional days and the medium was changed
after 48 hours of culture. PGEz was present in the culture medium of the experimental bones throughout the
culture period.
Preparation of the PGE2 Medium
Four milligrams of PGE2 (MW = 352; Upjohn, Kalamazoo, MI) were dissolved in 1 ml of absolute alcohol,
and 20 p1 of this solution was added to 19.98 ml of
supplemented BGJb medium. The final concentration of
M1 in
PGE2 in the medium therefore was 1.14 x
0.01% alcohol. A similar amount of alcohol was added to
the control medium.
Bone Histomorphometric Studies and 45Ca
Release Measurement
At the end of each day, five control and experimental
paired bones were removed for histomorphometric study
and aliquots of 50 pI of cultured medium of each well
was diluted in 10 ml of scintillation fluid and counted
for the presence of radioactive calcium. The data for
45Ca release are expressed a t the ratio of treated over
control bones.
Control and PGE2-treated bones were fixed in 40%
ethanol, dehydrated in graded alcohol, and embedded
without decalcification in methyl-methacrylate. Three
micron thick longitudinal sections were cut with an
Autocut Microtome (Jung, Germany) and stained with
toluidine blue (pH 3.0).
A morphological study was performed to evaluate the
cellularity of the explant. Measurements of the internal
diameter of the midshaft with a n ocular micrometer was
used to select the widest (most central) section for histomorphometry. The measurements were made at x 500
magnification with a Manual Optical Planimeter (MOP
3, Carl Zeiss, Germany). The following parameters were
recorded separately for cortical and medullary bone:
bone volume (% of whole tissue and cubic microns [p3]
number of osteoclasts per field (0.05 mm2) and extent of
osteoblastic surface (osteoblasts lining osteoid tissue)
along the periosteal surface (%I.
Statistical comparison between control and PGE2treated cultures was performed using the Student's t
test and the difference was considered significant when
P < 0.05.
Control Bone Cultures
A slight but unsignificant increase in bone volume (%
and cubic microns, p3) was recorded during the 4 days of
culture, both in the cortical and medullary bone. Medullary and cortical osteoclast numbers were low and
remained unchanged during the experiment. Similarly,
no changes were observed in the extent of periosteal
osteoblastic surface (Table 1).
PG&Treated Bone Cultures
In contrast, significant changes were recorded in the
bones cultured with PGE2 (Figs. 1, 2). Over the total
culture period (cumulative data of the 4 days in culture),
the number of cortical osteoclasts was significantly
higher than in the control bones (0.46 5 0.28 vs. 0.05 f
0.07, OCifield, P < 0.01) (all numbers are given as mean
standard deviation). However, despite this increase in
the number of osteoclasts, no significant changes occurred in the cortical bone volume (%) and amount (Fig.
1).Similarly, a significant increase in osteoclast numbers was recorded in the medullary bone (0.3 k 0.3 vs.
0.8 % 0.4,OC/field, P < 0.05). In this case, however, this
was associated with a significant decrease in medullary
bone (185 k 52 vs. 114 & 20, p3, P < 0.01) and bone
volume (17.7 f 3.3 vs. 9.8 f 2.0%, P < 0.01) (Fig. 2).
The extent of periosteal osteoblastic surface was significantly higher in the PGEz-treated bones (Table 1)and
numerous active osteoblasts, characterized by large
Golgi areas in a very basophilic cytoplasm, and new
bone formation, attested by increased osteoid, was prominent along the periosteal surface of the bones cultured
with PGE2 (Figs. 3,4).
Although osteoclast numbers increased both in the
medullary and cortical bone, the kinetics of that increase was different. A significant increase in medullary
osteoclasts was first observed after 24 hours in culture
(1.1 0.2 vs. 0.3 5 0.2, OC/field, P < 0.001); this
number remained unchanged and returned toward the
control level within the last 2 days (Fig. 2). In contrast,
the increase in cortical osteoclasts was slower and delayed in time, reaching a peak only after the third day
in culture (0.7 -+_ 0.4 vs. 0.5 f 0.05, OC/field, P < 0.01)
and then decreased (Fig. 1).
When the 45Ca release was compared with changes in
osteoclast numbers, a positive linear and significant correlation (r = 0.72, P < 0.01) was found with the cortical
osteoclasts but not with the medullary osteoclasts (Fig.
Finally, when the total bone volume was calculated
without separating cortical and medullary bone, a sig-
*** p<ooo1/c
** p<oo1 /c
- Control
-- PGE,
- Control
-- PGE,
* p<O.OI / c
i ,
45 I
Fig. 2. Effects of PGE2 on medullary bone in culture over a 4-day
Fig. 1. Effects of PGE2 on cortical bone in culture over a 4-day period.
Bars represent standard deviations; P < O.Ol/C = significantly differ- period. Bars represent standard deviations; /C = significantly different
ent from controls.
from controls.
medullary bone, this led to a significant bone loss, therefore indicating that bone formation was decreased relative to bone resorption. On the other hand, despite the
increase in the number of osteoclasts, no decrease in
cortical bone was measured and a n increase in periosteal osteoblastic surface was present, therefore demonstrating a parallel increase in bone formation a t this
site. The overall effect on the amount of bone present in
the cultured bones, however, was a net bone loss.
Our observations regarding the stimulation of bone
resorption by PGE2 are in agreement with those in
much of the literature (Klein and Raisz, 1970; Dietrich
et al., 1975; Rifkin et al., 1980; Holtrop and Raisz, 1979).
Few reports, however, have mentioned an increase in
bone formation.
The maintenance of a normal bone mass in the cortical
bone could be accounted for in two different ways. The
first would be to assume that the newly differentiated
osteoclasts are unable to resorb bone at a normal rate:
this is, however, unlikely, given the parallel increase in
45Ca release in the culture medium, strongly correlated
PGE2, added to the bone culture medium a t a concen- with osteoclast numbers in the cortex.
tration of
M, increased the number of osteoclasts
The only alternative hypothesis to explain the mainboth in the medullary and the cortical bone. In the tenance of cortical bone would be to assume that PGEz
nificant decrease in the bone volume of the bones cul3.4%,P < 0.01)
tured with PGE2 (35.2 4.4 vs. 27.5
was observed together with a significant increase in the
total number of osteoclasts (0.13 0.09 vs. 0.58 + 0.24,
OCIfield, P < 0.01) which was correlated with the release of 45Ca (r = 0.60 P < 0.001).
In summary, PGE2 added to the culture medium stimulated the differentiation of new osteoclasts both in the
cortical and medullary bone. Despite the increase in
cortical osteoclasts, a slight increase in the amount of
cortical bone was recorded and active osteoblasts forming new bone matrix along the periosteal surface were
prominent (Figs. 3, 4).On the other hand, the increase
in medullary osteoclasts was associated with a decrease
in medullary bone. An increase in 45Ca release in the
culture medium was also recorded and correlated to the
total and cortical number of osteoclasts but not with the
medullary osteoclasts.
TABLE 1. Effects of PGE2 on 45Carelease and bone histomorphometry of fetal rat long bones in culture
Day 0
45CaT/C ratio
Day 1
1.04 (0.13)
Bone volume (%)
Cortical bone
C 49.6 (3.2)
Medullary bone C 15.3 (1.0)
C 31.5 (6.3)
Amount of bone (.urn3)
Cortical bone
C 206 (76)
Medullary bone C 105 (26)
C 312(92)
50.5 (2.6)
49.8 (2.2)
16.2 (1.6)
12.1 (2.5)
33.0 (3.3)
27.8 (6.2)
241 (42)
205 (68)
174 (35)',*
114 (34)
319 (97)
No. of osteoclasts/field
Cortical bone
C 0
Medullary bone C
0.6 (0.4)
C 0.23 (0.16)
C 25.5 (10.4)
Day 2
1.45 (0.23)'
50.6 (1.6)
49.8 (1.2)
14.6 (2.6)
9.2 (1.0)'."*
32.4 (5.4)
26.3 (2.6)
199 (17)
251 (68)
133 (45)'.*
110 (17)'.*
332 (53)
361 (84)
0.05 (0.05)
0.08 (0.1)
0.5 (0.1)'z2,**
0.2 (0.2)
0.3 (0.2)
0.3 (0.3)
1.0 (0.4)'.*
0.17 (0.09)
0.16 (0.14)
0.46 (0.10)'-** 0.64 (0.09)'.2.***
20.7 (7.4)
23.1 (8.7)
27.5 (7.2)
36.7 (12.5)'.*
Day 3
1.91 (0.18)',2
51.7 (2.5)
51.2 (0.4)
16.8 (2.4)
7.8 (0.6)'****
35.7 (2.9)
27.2 (0.5)"**
281 (86)
288 (65)
194 (27)
105 (16)'.***
475 (72)
394 (72)
0.05 (0.05)
0.7 (0.4)'.**
0.2 (0.2)
0.7 (0.5)
0.12 (0.06)
0.74 (0.35)',*
22.2 (11.4)
35.1 (14.5)',*
Day 4
1.79 (0.43)'
51.8 (3.3)
50.7 (2.7)
20.2 (4.4)
10.5 (0.6)'.2**"
38.2 (4.1)
28.9 (4.5)a*
273 (95)
304 (98)
226 (49)
131 (9)'.**
499 (88)
435 (95)
1.6 (0.4)'
51.2 (2.5)
50.5 (1.7)
17.7 (3.3)
9.8 (2.0)'3**
35.2 (4.4)
27.5 (3.4F"*
250 (73)
264 176)
185 (52)
114 (20)'%**
435 (91)
379 (86)
0.05 (0.07)
0.05 (0.07)
0.4 (0.2)',**
0.5 (0.3)',**
0.2 (0.3)
0.3 (0.3)
0.5 (0.2)',*
0.8 (0.4)'.*
0.13 (0.09)
0.09 (0.05)
0.44 (0.12)',*** 0.58 (0.24)'*4'*
21.2 (10.4)
19.1 (9.1)',*
34.3 (13.2)',""
38.0 (19.5)
surface (%)
M)-treated bones, C , control bones. Numbers are means with standard deviations in parentheses.
'Significantly different from control.
:Significantly different from previous day.
P < 0.05.
P < 0.01.
< 0.001
a t the concentration used in this study stimulates not
only bone resorption but also bone formation along the
periosteum. We have indeed observed a significantly
higher periosteal osteoblastic surface in PGEz-treated
bones. This quantitative result is strongly supported by
the morphological observation of numerous active osteoblasts and new bone formation along the periosteum
of the bones cultured in the presence of prostaglandins.
This envelope-specific effect could be related to the concentration of PGE2 used in our study since Raisz and
Koolemans-Beynen (1974) and Goldhaber et al. (1973)
did not observe a stimulation of bone formation in vitro
at lower concentrations. However, it is important to
point out here that our results are actually not in contradiction with these previous reports since we observe an
overall bone loss that could correspond to a n overall
decrease in collagen synthesis when measurements are
made on the whole explant. This does not exclude a local
stimulatory effect a t the periosteum which these methods would not be able to detect. On the other hand,
Blumenkrantz and Sondergard (1972) reported a n in
vitro stimulation of bone collagen formation by PGEl
and similar observations were made in vivo in various
circumstances: Kafrawy and Mitchell (1977)observed a n
increase in both bone resorption and bone formation
after five injections of PGE2 per week for 2 weeks in
alveolar bone; Goodson et al. (19741, who reported some
extensive, although not osteoclastic, resorption areas
after seven daily injections over the calvaria of rats, also
mentioned intense bone formation along the periosFig. 3.Morphology of fetal rat long bones at the end of the culture teum, an observation that we have later confirmed usperiod. A,B) General views of the bones ( x 100). A) PGEz-treated; B) ing fluorescent labels (Baron et al., 1978). Finally, and
control medium. The medullary bone (M) is markedly decreased in t,he
cultures containing PGEz (A) as compared to control @3); ostewlasts more recently, long-term infusions of PGEl in children
(straight arrows) are large and numerous in PGEz-treated bones but have led to increased periosteal bone formation as asare also frequent in control bones. Along the periosteum (P), intense sessed by X rays (Ueda et al., 1980; Ringel et al., 1982).
proliferation of osteoblasts and formation of bone can be observed Therefore, it seems that PGE are able to stimulate bone
(curved arrows) in PGEz-treated bones. C ) Higher magnification
formation, both in vivo and in vitro, at given concentra( X 1,000)of large and numerous ostewlasts in the medullary bone of
PGEz-treated bones.
tions and maybe preferentially along the periosteum.
Fig. 4. Higher magnifications ( ~ 2 5 0of) the periosteal osteoblastic
reaction in PGEz-treated bones. A) Highly proliferative area along the
periosteum of PGEz-treated bones with large numbers of osteoblasts
(open arrows) and newly produced matrix (black arrows). B) Similar
bone-forming area in a control bone: presence of matrix (black arrows)
lined with osteoblasts but lack of intense cell proliferation. C) Osteoblastic proliferation (open arrow) along the periosteum (p) of PGE2treated bones with production of matrix (small black arrows); the
endosteum (e) shows little formation and large ostewlasts (black arrow).
Cortical Bone
-- Medullary Bone
45C0 Release
* p<0.02 / c
** p c o . 0 1
Fig. 5. Comparison of 45Ca release and osteoclast numbers in the
cortical and medullary areas of PGEz-treated bones in culture. Bars
represent standard deviations. /C = significantly different from
However, there was a clearly different response a t the
level of the endosteum: the total amount of bone present
in the medullary space decreased markedly during the
experiment and this was associated with a marked increase in the number of osteoclasts. Morphologically, no
signs of bone formation could be detected at this level.
A morphometric study performed on trabecular bone in
VX2 carcinoma-bearing rabbits also showed decreased
bone formation at this site (Wolfe et al., 1978).
These results would therefore indicate a differential
response of the periosteum and the endosteum to prostaglandins under our experimental conditions: both resorption and formation (bone turnover) would be
increased in the cortex, leaving the balance between
these two activities in equilibrium whereas only bone
resorption would be increased along the endosteum,
leading to marked medullary bone loss as well as an
overall bone loss when considering cortical and medullary bone together. A similar, but reversed, envelopespecific action has also been suggested for parathyroid
hormone and for thyroid hormones (Mosekilde and Melsen, 1978a,b).
Since similar studies have not been performed with
other bone-resorbing factors, it is not possible to make
conclusions on the specificity of P G E 2 in inducing this
differential response but our results nevertheless demonstrate that, under these experimental conditions,
prostaglandins can stimulate both formation and resorption in organ cultures.
This work was supported by grant #DE 04724 from
the NIH. The authors are grateful to Mrs. Lynn Neff for
her expert technical help and to Mrs. Barbara Devlin
for typing the manuscript.
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