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15
Hormonal Effects on Bone Cells
Teresita Bellido1 and Kathleen M. Hill Gallant2
1
Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA 2Department of Anatomy and Cell
Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
INTRODUCTION: DIRECT VERSUS can generate both catabolic and anabolic effects on bone,
INDIRECT EFFECTS OF HORMONES ON depending on the temporal profile of its increase.
BONE CELLS Continuous (or chronic) elevations in PTH, as in primary
or secondary hyperparathyroidism, increase the rate of
Systemic hormones can affect bone either directly or bone remodeling, and can result in loss of bone. In con-
indirectly. Direct action occurs through receptors trast, intermittent increases of PTH in the blood, as
expressed in bone cells. Indirect action occurs when a achieved by daily injections of the pharmaceutical agent
hormone modulates mineral homeostasis through regu- teriparatide [recombinant human PTH; rhPTH(134)],
lation of calcium and phosphate absorption by the intes- results in bone gain.
tine and excretion or reabsorption by the kidney. The The high bone remodeling rates and bone loss result-
goal of this chapter is to discuss the current knowledge ing from chronic PTH elevation are associated with
about the direct effects of hormones on the skeleton. excessive production and activity of both osteoclasts and
osteoblasts. The enhancement of osteoclast activity out-
paces that of osteoblasts and thus results in a negative
PARATHYROID HORMONE basic multicellular unit (BMU) balance (see Chapter 4,
Fig. 4.11). Conversely, the primary effect of intermittent
Parathyroid hormone (PTH) is a peptide hormone PTH elevation is a rapid increase in the number and
that controls the minute-to-minute level of ionized cal- activity of osteoblasts and in bone formation, leading to
cium in the circulation and extracellular fluids. PTH is net bone gain. The mechanism of this anabolic effect is
secreted by the chief cells of the parathyroid gland in attributed to the ability of PTH to promote proliferation
response to low levels of calcium in the blood. The of osteoblast precursors, inhibit osteoblast apoptosis,
two main target tissues of PTH are bone and kidney. reactivate lining cells to become matrix synthesizing
By binding to receptors in cells of these tissues, PTH osteoblasts, or a combination of these effects (see below).
induces responses leading to an increase in blood In humans, intermittent PTH administration stimulates
calcium concentrations. This increase in circulating bone formation by increasing the bone remodeling rate
calcium, in turn, feeds back on the parathyroid gland and the amount of bone formed by each BMU in a pro-
to reduce PTH secretion. cess named remodeling-based formation. PTH also stimu-
lates bone formation not coupled to prior resorption,
referred to as modeling-based formation. The latter mecha-
Actions of Parathyroid Hormone on Bone nism appears to be more evident in rodents.
Apoptotic
Bone formation osteoblast
Hematopoietic osteoclast
Reactivation of Lining Cells by Parathyroid Mature
precursor osteoclast
Hormone
Other mechanisms besides downregulation of Sost
expression and osteoblast survival are likely to contrib- Bone resorption
ute to the profound skeletal effects of PTH on bone
FIGURE 15.2 Parathyroid hormone stimulates bone resorption
formation. One of these additional mechanisms is the by regulating the expression of pro- and anti-osteoclastogenic cyto-
conversion of inactive lining cells that cover the quies- kines in cells of the osteoblastic lineage. Osteoclast differentiation
cent surface of bone into matrix-producing osteoblasts from hematopoietic precursors of osteoclasts is stimulated by the
(Fig. 15.1). This mechanism was suggested by indirect RANK ligand [tumor necrosis factor ligand superfamily member 11/
studies showing that PTH increases osteoblast number receptor activator of the NF-κB ligand (RANKL)] and macrophage
colony-stimulating factor 1 (M-CSF) and inhibited by osteoprotegerin
on bone surfaces concomitantly with a decrease in (OPG). Parathyroid hormone (PTH), acting on receptors expressed in
lining cell number, without detectable changes in cell cells of the osteoblastic lineage, increases osteoclast production and
proliferation. A more recent lineage-tracing study bone resorption by increasing RANKL and inhibiting OPG. 1, stimu-
showed that PTH is able to convert lining cells into lation; 2, inhibition.
and that deletion of RANKL from osteocytes leads to conversion of androgens to estrogens by cytochrome
osteopetrosis. Moreover, RANKL expression, osteoclast P450 aromatase. Adipose tissue is the main tissue for
number, and bone resorption are elevated in transgenic estrogen production in men and for extraovarian estro-
mice with constitutive activation of the PTH1-R in osteo- gen production in women.
cytes. These findings raise the possibility that at least Androgens are sex steroids secreted by the testes in
part of the effects of PTH on osteoclast differentiation men, the ovaries in women, and the adrenal glands in
and resorption are due to osteocytic RANKL regulation. both men and women. Testosterone, the main andro-
gen in men, is secreted primarily by the testes (approx-
imately 95% of total testosterone). In women, only
SEX STEROIDS about 25% of testosterone comes from the ovaries;
another 25% comes from the adrenal glands, but half
In the 1940s, Fuller Albright made the association of total testosterone in women comes from conversion
between women’s loss of estrogen at menopause and of other sex steroids, such as dehydroepiandrosterone
bone loss. For decades, this association was believed to (DHEA) and androstenedione, by peripheral tissues
be indirect, until the discovery in the late 1980s that such as adipose tissue.
estrogens bind directly to bone cells, indicating a direct Most testosterone is bound to proteins in the circu-
effect of estrogen on the skeleton. In men, the gradual lation. Approximately half is bound with high affinity
reduction in androgen secretion with aging is associ- to steroid hormone-binding globulin, with the other
ated with bone loss. Some of the effects of androgens half bound with low affinity to albumin. Only 12%
are due to their conversion to estrogen. However, bone of testosterone is free (unbound) in the circulation.
cells express receptors that specifically bind androgens Bioavailable testosterone refers to both free testoster-
and mediate their biological effects independently of one and albumin-bound testosterone. Free testosterone
estrogens. This section addresses the general and sex- diffuses passively through cell membranes and binds
specific effects of the main sex steroid hormones affect- to the androgen receptor. Testosterone can be metabo-
ing skeletal tissue: androgens and estrogens. lized in peripheral tissues to the potent androgen,
dihydrotestosterone by 5-alpha-reductase, or to 17β-
estradiol by cytochrome P450 aromatase.
Sex Steroid Production
Sex steroid hormone synthesis begins by hydrolysis
of cholesterol esters and uptake of cholesterol by the
Sex Steroid Receptor Signaling
mitochondria of target tissue cells. Cholesterol is Sex steroid signaling occurs through genotropic
metabolized to pregnenolone, which is further metabo- and nongenotropic signaling pathways (Fig. 15.3).
lized to produce all sex steroid hormones. Estrogens Genotropic signaling occurs when the sex steroid ligands
are sex steroids secreted by the ovaries in women and bind to the sex steroid receptors, which then dimerize
to a small extent by the testes in men. Over 80% of and translocate to the nucleus to initiate gene transcrip-
estrogen in men is produced through peripheral tion. Dimerized sex steroid receptors can bind directly to
IL-6
NF-kB Osteoblast/osteocyte
survival
Sex hormone effects on longitudinal growth FIGURE 15.4 Concept model of the
effects of sex hormones during growth.
Early Puberty
Late puberty Early in puberty, low levels of estrogen
Hypothalamus +
pituitary and testosterone stimulate longitudinal
E ERα bone growth. In both sexes late in puberty,
GH-IGF-1 estrogen stimulates epiphyseal closure.
AR E ERα
Axis Estrogen is stimulatory to bone formation
T > at the endosteal surface and inhibitory at
Longitudinal Epiphyseal the periosteal surface of bone, whereas tes-
growth closure tosterone is stimulatory at the periosteal
surface. AR, androgen receptor; GH,
somatotropin/growth hormone; E, estro-
Sex hormone effects on bone surfaces gen; ERα/β, estrogen receptor α/β; IGF-I,
insulin-like growth factor I; T, testosterone.
See text for details.
ERβ Cortical
thickening
with endosteal
– contraction
ERα Growth
E
+
T AR
+ Cortical
thickening
with periosteal
expansion
TABLE 15.1 Bone Loss in Men and Women with Aging and Sex-Steroid Loss
Life Stage Compartment Rate of Loss Amount of Loss
510 years postmenopause Q Cancellous; 46%/years; Cancellous . cortical
Cortical 12%/years
Older age Q Cancellous; 12%/years; Cortical . cancellous
Cortical 12%/years
Older age R Cancellous; 12%/years; Cortical . cancellous
Cortical 12%/years
At the beginning of puberty, both estrogen and tes- TABLE 15.2 Effects of Sex Steroid Deficiency on Bone Cells
tosterone activate the somatotropin/growth hormone
Cell Type Number Birth Death
(GH)-IGF-I axis to stimulate longitudinal bone growth.
The effects of estrogen during growth are dependent Osteoclasts Increased Increased Decreased
on the stage of development. Early in puberty, estro- Osteoblasts Increased Increased Increased
gen (at relatively low levels in girls compared with
Osteocytes Unknown Unknown Increased
later puberty) signaling through ERα in the hypothala-
mus and pituitary is necessary for GH secretion, which Supply of osteoclasts exceeds demand.
acts directly and indirectly through IGF-I to increase High rate of bone remodeling.
Osteoclasts Induction of apoptosis (Fas ligand and ERK/JNK Genotropic and nongenotropic
activation)
Stromal/osteoblastic cells and Inhibition of pro-osteoclastogenic cytokine production Genotropic, mediated by receptor-transcription
T lymphocytes (IL-1, IL-6, and TNFα) factor interaction
Osteoblasts and osteocytes Inhibition of apoptosis (ERKs and PI3-K) Nongenotropic
ERK, extracellular signal-regulated kinase; IL-1/6, interleukin-1/6; JNK, c-Jun N-terminal kinase; PI3-K, phosphoinositide 3-kinase.
is related to the lifetime of the BMU) is determined by including the mitogen-activated protein kinase
the supply of osteoclast and osteoblast precursors, (MAPK)-c-Jun N-terminal kinase (JNK) and TNF
whereas the depth of the BMU’s erosion lacunae ligand superfamily member 6 (Fas ligand) pathways.
depends on the timing of apoptosis in mature osteo-
clasts. In estrogen deficiency, the supply of osteoclast
precursors is enhanced, resulting in the origination of Effects of Estrogens and Androgens on
more BMUs per unit bone area (i.e. a higher activation Osteoblasts and Osteocytes
frequency), and there are more osteoclasts and osteo-
blasts contributing to extend the progression of each In contrast to their proapoptotic effect on osteo-
BMU. Moreover, osteoclasts live longer, resulting in clasts, estrogens and androgens inhibit apoptosis in
deeper resorption pits and delayed BMU reversal to the osteoblasts and osteocytes (Fig. 15.3; Table 15.3). The
formation phase. Furthermore, osteoblast apoptosis is mechanism of this survival effect involves rapid activa-
increased and thus bone formation is disproportion- tion of survival kinases ERKs and PI3-K. This is fol-
ately lower compared to resorption, contributing to a lowed by phosphorylation of the proapoptotic protein
negative balance within each remodeling cycle and Bad, which leads to inactivation of the apoptotic prop-
leading to bone loss. The prevalence of osteocyte apo- erties of the protein, and phosphorylation and activa-
ptosis is also increased, adding to the bone fragility that tion of the transcription factors ETS domain-containing
characterizes conditions of loss of sex steroids. protein (Elk) and CCAAT/enhancer-binding protein
beta (C/EBP β), with subsequent changes in gene
expression. These kinase-mediated posttranslational
and transcriptional effects are required for estrogen-
Effects of Estrogens and Androgens on induced survival of osteoblasts and osteocytes.
Osteoclasts
Consistent with the increase in osteoclasts and bone
resorption induced by sex steroid deficiency, estrogens GLUCOCORTICOIDS
and androgens decrease the number of osteoclasts
in vivo and in vitro (Table 15.3). The cellular mecha- Glucocorticoids are produced and released by the
nism of reduction of osteoclasts involves inhibition of adrenal glands in response to stress. They regulate
osteoclast generation combined with induction of oste- numerous physiologic processes in a wide range of
oclast apoptosis. Estrogens decrease the production of tissues. Among several effects, these hormones exert
interleukin-1 (IL-1,) IL-6, and tumor necrosis factor profound immunosuppressive and anti-inflammatory
(TNF-α) in cells that support osteoclast formation, actions and induce apoptosis in many cell types,
resulting in inhibition of proliferation and the differen- including T lymphocytes and monocytes. Because of
tiation of osteoclast precursors toward mature osteo- these properties, exogenous glucocorticoids are exten-
clasts. The inhibitory effect of estrogens on cytokine sively used for the treatment of immune and
production is mediated by an interaction between the inflammatory conditions, the management of organ
estrogen receptor and NF-κB and regulation of gene transplantation, and as components of chemotherapy
expression mediated by this transcription factor regimens for hematological cancers. However, long-
(Table 15.3). Androgens exert similar effects as estro- term use of glucocorticoids is associated with severe
gens on the production of pro-osteoclastogenic cyto- adverse side effects in several organ systems. In partic-
kines. In addition, estrogens induce apoptosis in ular, prolonged use of exogenous glucocorticoids leads
mature osteoclasts by acting directly on these cells. to a dramatic loss of bone mineral and strength,
Current evidence indicates that estrogens induce osteo- similar to endogenous elevation of glucocorticoids in
clast apoptosis by activating proapoptotic pathways, Cushing disease.
Osteocytes
• increased osteocyte apoptosis
Epidemiology and Progression of Glucocorticoid- and the rate of bone formation (Fig. 15.5). Several
Induced Bone Disease mechanisms account for this remarkable decrease in
bone formation, including reduced osteoblastogenesis,
The prevalence of glucocorticoid-induced osteopo- decreased activity of osteoblasts, and increased apo-
rosis has changed markedly in recent years due to the ptosis in osteoblasts. In addition, the prevalence of
increased therapeutic use of these agents. Around osteocyte apoptosis is augmented with glucocorticoid
1950, bone loss due to glucocorticoid excess was rare treatment. Mapping of apoptotic osteocytes demon-
and more than 90% of the cases were due to endoge- strates that they accumulate in areas juxtaposed to the
nous hypercortisolism. Today, glucocorticoid-induced subchondral femoral bone that collapses in patients
osteoporosis is almost entirely an iatrogenic disorder with osteonecrosis, suggesting that osteocyte apoptosis
and the most common cause of secondary osteoporo- might contribute to osteonecrosis and to the increase
sis. It occurs irrespective of the original disease being in bone fragility (Fig. 15.5).
treated and all patients are susceptible, even if they do The proapoptotic effect of glucocorticoids on osteo-
not present the usual risk factors for bone loss. blasts and osteocytes results from direct actions of the
The loss of bone mineral upon glucocorticoid steroids on cells of the osteoblastic lineage, as the proa-
administration is biphasic. BMD decreases rapidly at a poptotic effect of glucocorticoids is readily demonstra-
rate of 612% during the first year and more slowly ble in cultured osteocytes and osteoblasts. Furthermore,
thereafter, at a rate of approximately 3% per year. A transgenic mice overexpressing corticosteroid 11-beta-
total of 3050% of patients receiving long-term gluco- dehydrogenase isozyme 2, an enzyme that inactivates
corticoid therapy present one bone fracture. The risk of glucocorticoids, in osteocytes and osteoblasts are pro-
fracture increases as much as 75% during the first 3 tected from glucocorticoid-induced apoptosis and
months of treatment, before significant decreases in changes to bone mass and fragility.
BMD are detected. Moreover, 25% of patients also The initial rapid bone loss induced by glucocorti-
present with collapse of the femoral head associated coid excess is also associated with increased osteoclasts
with osteonecrosis of the hip. and elevated resorption (Fig. 15.5). This results from
an inhibition of osteoclast apoptosis by glucocorticoid
treatment. In contrast, during the slower phase of bone
loss seen with long-term treatment, osteoclasts are not
Glucocorticoids and Bone Cells increased and may even decrease in number. This is
The bone fragility syndrome associated with caused by decreased osteoclast generation resulting
glucocorticoid-induced osteoporosis is characterized from reduction in the number of osteoblastic cells that
by a marked reduction in the number of osteoblasts support osteoclast formation.
with increased fracture risk. Even in the healthy popula- IL-8, prostaglandin E2 (PGE2), and RANKL, which pro-
tion, there is evidence to suggest that high-normal range mote osteoclastogenesis. It is unclear whether the
thyroid status is associated with reduced BMD and effects of T3 promote bone resorption only indirectly
increased risk of fracture, suggesting that thyroid status through osteoblastic mediation of osteoclastogenesis or
affects bone status in both physiologic and pathologic whether there are direct effects of T3 in osteoclasts. The
situations. effect of TSH on osteoblasts is unknown, as studies
Specific thyroid hormone transporters are expressed have shown both inhibitory effects and stimulatory
in osteoblasts, osteoclasts, and growth plate chondro- effects on osteoblastogenesis. Similarly, some studies
cytes at different states of cell differentiation, indicat- have shown an inhibitory effect of TSH on osteoclasts
ing that thyroid hormones can enter these cells. TRα1 and bone resorption, but this has not been consistently
and TRβ1 are expressed in osteoblasts, osteoclasts, observed across all studies. T3 inhibits proliferation
growth plate chondrocytes, and bone marrow stromal and promotes hypertrophic differentiation of growth
cells (BMSCs). It is unknown whether TRs are plate chondrocytes. Therefore, in hypothyroidism,
expressed in osteocytes. Additionally, TSHR is endochondral ossification and linear growth are
expressed in osteoblasts and osteoclasts, suggesting impaired, whereas in hyperthyroidism, endochondral
potential direct effects of TSH in bone cells ossification is enhanced, resulting in short stature due
(Table 15.4). to premature closure of the growth plates (Table 15.4).
In osteoblasts, T3 increases expression of alkaline
phosphatase (ALP), fibroblast growth factor receptor 1
(FGFR-1), insulin-like growth factor I (IGF-I), osteocal- SOMATOTROPIN/GROWTH HORMONE
cin, osteopontin, type I collagen, and matrix metallo-
proteinases 9 and 13 (MMP-9 and MMP-13). In BMSCs Somatotropin/GH and IGF-I are important regula-
and mature osteoblasts, T3 increases expression of IL-6, tors of bone during growth and throughout life. Many
Osteoblasts Yes Yes m Osteocalcin Evidence for both stimulatory and inhibitory effects
m Osteopontin
m Type 1 collagen
m ALP
m IGF-1
m MMP-9/13
m FGFR-1
m RANKL
m IL-6/8
m PGE2
Osteoclasts Yes Yes Indirect effects through osteoblasts Inhibitory?
Direct effects on osteoclast?
Osteocytes ?
ALP, alkaline phosphatase; FGFR-1, fibroblast growth factor receptor-1; IGF-I, insulin-like growth factor I; IL-6/8, interleukin-6/8; MMP-9/13, matrix
metalloprotease 9/13; PGE2, prostaglandin E2; RANKL, RANK ligand/tumor necrosis factor ligand superfamily member 11; T3, 3,5,30 -l-triiodothyronine; TR,
thyroid hormone receptor; TSH, thyrotropin/thyroid-stimulating hormone; TSHR, thyrotropin/TSH receptor.
may influence bone metabolism indirectly through its number of substrate proteins that serve as effector
actions on PTH, 1,25(OH)2D3, and phosphate handling. molecules.
GH helps to maintain PTH secretion and circadian Establishing the importance of insulin for bone
rhythm and increases the production of 1,25(OH)2D3 independent of IGFs is difficult due to their overlap-
by increasing 1α-hydroxylase and inhibiting 24- ping functions. However, type 1 diabetes mellitus
hydroxylase. GH also increases phosphate retention by (T1DM) patients, who are insulin deficient due to loss
increasing the renal maximal reabsorption threshold of pancreatic beta cell mass and function, have lower
for phosphate. Together, these actions of GH favor bone mass and are at increased risk for early onset
bone formation. osteoporosis and increased fracture risk. In addition,
animal models of T1DM show that bone formation is
reduced, providing evidence for a relationship
between insulin and bone, although these animals also
INSULIN have low circulating IGF-I.
IRs have been identified in osteoblasts, and treating
Insulin and IGFs are highly homologous, as are osteoblasts with insulin increases collagen synthesis
their receptors and their functions. The effects of IGFs and ALP activity. Global IR knockout mice are not via-
on bone are discussed in Chapter 3. In this chapter, the ble past the early postnatal period, but studies of cell-
more direct effects of insulin on bone cells will be specific IR and IGF-IR deletion in osteoblasts have
discussed. been informative about the individual roles of insulin
Insulin is a peptide hormone secreted by pancreatic signaling versus IGF-I signaling. These studies show
beta cells in response to increased concentrations of that diminished insulin signaling in osteoblasts results
glucose in blood. Insulin increases glucose uptake into in reduced cancellous bone volume, with no defects in
target tissues and inhibits the release of stored energy. mineralization but reduced osteoblast number. On the
Insulin (and IGFs) signals through the insulin receptor other hand, diminished IGF-I signaling in osteoblasts
(IR), a cell surface tyrosine kinase receptor present in results in reduced cancellous bone volume and under-
two isoforms: α and β. IRs exist as either homodimers mineralized bone, but with a normal number of osteo-
of the same IR isoform, or as heterodimers of IRα and blasts. Cultured IR-deficient osteoblasts exhibit
IRβ or an IR with insulin-like growth factor-1 receptor impaired proliferation and differentiation, whereas
(IGF-IR). Signaling transduction occurs by conforma- wild-type osteoblasts treated with insulin have
tional changes upon ligand binding, which result in increased proliferation and differentiation (Fig. 15.7A).
autophosphorylation, followed by increased kinase More recently, insulin signaling in osteoblasts has
activity of the receptor, and phosphorylation of a been implicated in controlling whole body glucose
Pancreatic
↑ unOC beta cells
↑ Bone formation and
mineralization
↑ Insulin
sensitivity ↑ Insulin
metabolism through an osteocalcin-dependent mecha- provide sufficient calcium and phosphate for normal
nism. Insulin signaling in osteoblasts increases the mineralization, particularly by mediating intestinal cal-
production of osteocalcin, which in turn acts on the cium and phosphate absorption. The role of 1,25
pancreas to increase insulin production. Additionally, (OH)2D3 on mineral homeostasis is discussed in
insulin signaling in osteoblasts decreases OPG and Chapter 13. Here, the direct effects of 1,25(OH)2D on
thus increases osteoclastic bone resorption. During bone cells are discussed.
bone resorption, undercarboxylated osteocalcin, which VDR is present in cells of the osteoblastic lineage,
is considered the active hormonal form of osteocalcin including osteoblast progenitor cells, osteoblast precur-
regarding glucose metabolism, is liberated from the sors, and mature osteoblasts. 1,25(OH)2D3 signaling in
bone matrix. This provocative animal experimentation osteoblastic cells increases production of RANKL and
demonstrates a novel metabolic function of bone. decreases the production of OPG, thus increasing
However, the relative importance of insulin signaling RANKL-RANK-mediated osteoclastogenesis. This action
in bone to overall glucose metabolism and the validity of 1,25(OH)2D3 is consistent with the actions of PTH and
of the hypothesis in humans remains to be determined 1,25(OH)2D3 to increase serum calcium by liberating cal-
(Fig. 15.7B). cium from bone mineral.
1,25(OH)2D3 signaling can also directly affect
bone formation. 1,25(OH)2D3 increases production of
1,25-DIHYDROXYVITAMIN D3 RUNX2, an essential transcription factor for osteoblast
differentiation. Transgenic mice that overexpress VDR
1,25-Dihydroxyvitamin D3 [1,25(OH)2D3 or cholecal- in osteoblastic cells have increased bone formation.
ciferol] is a steroid hormone derived from vitamin D Though the main role of 1,25(OH)2D3 in promoting
in the diet or from subcutaneous synthesis. Vitamin D bone mineralization is through increasing intestinal
undergoes hydroxylation in the liver to produce 25 calcium and phosphate absorption (as evidenced by
(OH)D3, the serum indicator of vitamin D status, and a the high-calcium/phosphate rescue diet in the VDR
second hydroxylation in the kidney to produce 1,25 knockout mice), 1,25(OH)2D3 has also been shown to
(OH)2D3, the hormonally active vitamin D metabolite. have direct effects on osteoblasts to increase produc-
1,25(OH)2D3 signals by binding to the vitamin D recep- tion of osteocalcin and osteopontin, proteins involved
tor (VDR), which is a member of the superfamily of in bone mineralization (Fig. 15.8). Conversely, studies
nuclear receptors. VDR knockout mice develop hypo- have shown that high dose 1,25(OH)2D3 actually
calcemia, secondary hyperparathyroidism, and rickets, inhibits osteoblastic bone mineralization. Therefore,
indicating a role for 1,25(OH)2D3 in bone mineraliza- the direct effects of 1,25(OH)2D3 on bone are diverse,
tion. However, a diet high in calcium and phosphate and can affect both bone resorption and formation pro-
rescues the abnormal mineral biochemistries and bone cesses. Its beneficial effects occur within a defined win-
phenotype in the VDR knockout mouse, indicating dow, and either high or low levels can be detrimental
that the main effects of 1,25(OH)2D3 on bone are to to bone.
Mature osteoclasts
Bone mineralization
Bone resorption
↑ Serum Ca2+
Local effects
of leptin in bone marrow
Peripheral Leptin Central
signaling signaling
p
Leptin
LEPR LEPR
BMSC Hypothalamus Adipocytes
Stromal cells
Bone
Apoptosis
marrow
ADRβ1 ↑ Bone resorption
ADRβ2 ↓ Bone formation
Adipocyte Osteoblast
lineage lineage
osteoblasts
LEPR
↑ OPG ↓ Cancellous bone ↑ Cortical bone
↓ RANKL ↓ OB activity formation
Osteoblasts ↑ Bone remodeling
↓ Osteoclastogenesis ↑ Cortical
bone formation
FIGURE 15.9 Concept model of central and peripheral effects of leptin on bone and local effects of leptin in bone marrow. Leptin
secreted by body fat adipocytes increases bone formation through peripheral signaling and has dual-effects on bone through central signaling.
Leptin produced locally by adipocytes in the bone marrow increases stromal cell apoptosis, increases bone resorption, and decreases bone for-
mation. BMSC, bone marrow stromal cell; LEPR, leptin receptor; OB, osteoblast; OPG, osteoprotegerin; RANKL, tumor necrosis factor ligand
superfamily member 11/receptor activator of the NF-κB ligand.
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