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Hormonal Regulation of Bone Mineral Homeostasis
a report by
Daniel D Bikle, MD, PhD
Professor of Medicine and Dermatology, Veterans Affairs Medical Center and University of California, San Francisco
Simply stated, regulation of bone mineral homeostasis refers to controlling
the intra- and extra-cellular levels of two ions—calcium and phosphate—with
three hormones: parathyroid hormone (PTH), the active metabolite of vitamin
D 1,25 dihydroxyvitamin D (1,25(OH)2D3), and fibroblast growth factor 23
(FGF23) acting on three target tissues, i.e. bone, intestine, and kidney (see
Figure 1). This simple conceptual framework only partially reflects the true
situation. Other ions are involved: pH, sodium, potassium, magnesium,
chloride, bicarbonate, and sulfate all alter the cellular handling of calcium and
phosphate. Likewise, other hormones including calcitonin, prolactin,
glucocorticoid hormones, growth hormone, insulin, insulin-like growth
factors (IGFs), and a large number of cytokines contribute in important ways
to the regulation of bone mineral homeostasis. Finally, we now recognize that
a large number of tissues other than bone, intestine, and kidney are target
tissues for the calciotropic hormones in ways that contribute to bone mineral
homeostasis. However, in this short article I will focus on the interactions
among PTH, 1,25(OH)2D3, and FGF23 as they regulate calcium and phosphate
levels through actions on bone, intestine, and kidney.
Integration of Hormone Action at the Tissue Level
Figure 1 introduces the major hormones PTH, 1,25(OH)2D3, and FGF23
regulating serum calcium and phosphate levels through their actions on bone,
intestine, and kidney. PTH is secreted by the parathyroid glands. Vitamin D is
produced from 7-dehydrocholesterol in the skin by a photochemical reaction
involving ultraviolet B radiation (UVB) (sun is the natural source of UVB). The
liver, among other tissues—including the skin—converts vitamin D to the major
circulating form 25 hydroxyvitamin D (25OHD). The kidney is the major source
of 1,25(OH)2D3 for the circulation, although a variety of tissues, including a
number of epithelial and immunoregulatory cells, possess the enzyme
CYP27B1, which is capable of converting 25OHD to 1,25(OH)2D3. FGF23 is
thought to originate primarily from osteoblasts and osteocytes, although the
source of this relative newcomer to the list of calciotropic hormones is still
under active investigation and other cells express it. Calcium and phosphate
enter the blood from the intestine, are excreted by the kidney, and are stored
in the body principally in bone. In order to maintain homeostasis, the net
absorption of calcium and phosphate by the intestine must be precisely
balanced by net excretion of these ions by the kidney.
Absorption of these ions by the gut is not a continuous process, but
depends on dietary intake. The efficiency with which absorption occurs
for a given dietary load is the regulated variable. Glomerular filtration of
these ions by the kidney is relatively constant and dependent on overall
renal function, so the control takes place in adjusting the efficiency with
which these ions are reabsorbed from the glomerular filtrate as it passes
through the proximal tubule, thick and thin limbs of Henle’s loops (TALH),
© TOUCH BRIEFINGS 2008
distal tubule, and collecting ducts. Bone provides the major buffer for
maintaining relatively constant blood levels of these ions. This is achieved
by balancing bone formation, which deposits these ions in bone with
bone resorption, which releases these ions to the blood stream. Although
each tissue has distinct mechanisms and molecules by which it
contributes to bone mineral homeostasis, some common themes are
found, at least at the level of protein families. Therefore, TRPV6
(dominant in intestine) and TRPV5 (dominant in kidney) are highly
homologous calcium channels in the apical membranes of their
respective epithelial cells and play critical roles in calcium absorption
(intestine) and reabsorption (kidney), respectively.1 Similarly, calbindins
are a family of homologous proteins initially thought to play important
roles in the intracellular transport of calcium through the epithelia of the
intestine and kidney, with different calbindins in these different tissues,
although recent data suggest their role in transcellular transport may be
limited. 2,3 Different but homologous plasma membrane calcium
adenosine triphosphatases (ATPases), calcium pumps (PMCA), reside in
the basolateral membranes of the epithelia of the intestine and kidney to
transport the calcium out of the cell and into the bloodstream. Finally,
different but homologous sodium/phosphate co-transporters reside in
the apical membranes of the epithelia of the intestine and kidney to
regulate phosphate absorption and reabsorption.4
Little is known about the role, if any, of these protein families in bone. The
expression and function of these proteins are highly regulated, in
particular by the calciotropic hormones. Not surprisingly, there are sensors
in these tissues that, along with hormonal regulation, control these
processes. The best studied of these sensors is the calcium-sensing
receptor found in the parathyroid gland, bone, intestine, and kidney,
among other tissues.5 A sensor for phosphate is less clearly demonstrated,
but probably exists in some or all of these tissues. Various hormones act
on the tissues by different mechanisms, as I will discuss below. However,
Daniel D Bikle, MD, PhD, is a Professor of Medicine and
Dermatology at the Veterans Affairs Medical Center and
University of California, San Francisco, where he is also a staff
physician in the Endocrine/Metabolism Division and manages a
research laboratory focused on hormonal regulation of cell
function. His areas of interest include the molecular mechanisms
by which calcium and vitamin D regulate keratinocyte
differentiation and parathyroid hormone and insulin-like growth
factor-I regulate bone development and remodeling. Professor
Bikle received his MD and PhD from the University of Pennsylvania in Philadelphia and undertook
his residency training in medicine at the Peter Bent Brigham Hospital in Boston.
E: [email protected]
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Figure 1: Bone Mineral Homeostasis—The Players
Gut
Bone
Blood
Ca, P
25 OHD
FGF23
PTH
Parathyroid
glands
Kidney
Urine
Ca
1,25(OH)2D
P
25 ODH = 5-hydroxyvitamin D.
Blood levels of calcium (Ca) and phosphate (P) are primarily controlled by three hormones—1,25
dihydroxyvitamin D (1,25(OH)2D3), parathyroid hormone (PTH), and fibroblast growth factor
(FGF23)—acting on three target tissue: bone, gut, and kidney. Ca and P are absorbed from the
diet by the intestine, excreted by the kidneys, and stored in bone.
Figure 2: Bone Mineral Homeostasis—Hormonal Feedback Loops
Gut
Bone
+
25 OHD
FGF23
PTH
–
Kidney
Parathyroid
glands
–
+
1,25(OH)2D
25 ODH = 5-hydroxyvitamin D.
The hormones regulating bone mineral homeostasis each have feedback loops to regulate their
levels. Parathyroid hormone (PTH) stimulates, whereas fibroblast growth factor (FGF23) inhibits,
1,25 dihydroxyvitamin D (1,25(OH)2D3) production by the kidney. In turn, 1,25(OH)2D3
stimulates FGF23 production by bone while inhibiting PTH production.
their effects are well co-ordinated to ensure an increased supply of bone
minerals during periods of growth, steady-state levels during middle life,
and gradual loss during aging.
Hormonal and Ionic Feedback Loops
Figure 2 shows the feedback loops that operate among the calciotropic
hormones. PTH is the major regulator of 1,25(OH)2D3 production by the
kidney. This regulation appears to be genomic and mediated by protein kinase
A phosphorylation of transcription factors that act on the proximal region of
the CYP27B1 promoter.6 Non-renal sites of 1,25(OH)2D3 production such as
the keratinocyte and macrophage do not have PTH receptors, and so their
CYP27B1 expression is not regulated by PTH, at least not directly.7 On the other
hand, PTH production is inhibited by 1,25(OH)2D3, again at the transcriptional
level.8 The relationship between FGF23 and 1,25(OH)2D3 is the reverse, with
FGF23 inhibiting CYP27B1 activity and 1,25(OH)2D3 stimulating FGF23
72
production.9 FGF23 requires both specific FGF receptors (FGFR1c, 3c, and 4)
and Klotho as a co-receptor.10 To my knowledge, regulation of CYP27B1
expression by FGF23 outside the kidney has not been reported, limited perhaps
by the lack of Klotho in these tissues. However, the parathyroid gland expresses
both FGFRs and Klotho, and recent studies indicate that FGF23 inhibits PTH
production and secretion.11 PTH may stimulate FGF23 secretion in that serum
levels of these hormones correlate in models of hyper-parathyroidism,12 but a
direct regulation by PTH of FGF23 expression has not been established. In
addition to the hormonal feedback loops are the feedback loops involving
calcium and phosphate (see Figure 3). Both calcium and phosphate may have
direct actions to suppress CYP27B1 activity in the kidney. However, their
major influences are likely to be indirect: calcium suppressing CYP27B1
expression by suppressing PTH production and secretion, and phosphate
suppressing CYP27B1 expression by stimulating FGF23 production and
secretion. Phosphate may also stimulate PTH secretion directly, but this action
is less established than the inhibitory effects of calcium on PTH secretion.
Intestinal Absorption of Calcium and Phosphate
1,25(OH)2D3 stimulates intestinal calcium and phosphate absorption,13 and
acts through both genomic and non-genomic mechanisms to achieve this
regulation. The mechanism for calcium absorption has been better studied
than that of phosphate absorption. Both transcellular and paracellular
pathways are involved in calcium absorption, but much of what we know
about vitamin D regulation focuses on the transcellular process. Calcium
transport through the intestinal epithelial cell involves a three-step process:
getting calcium into the cell, moving it through the cell without initiating toxic
events, and discharging the calcium into the bloodstream against a steep
electrochemical gradient. The calcium channel TRPV6 is instrumental to gating
calcium flux into the cell, and this process may be regulated by calmodulin and
facilitated by the major calmodulin-binding protein in the microvillus: brush
border myosin I. Calcium transport through the cell is facilitated by calbindins
that have been found in endocytic vesicles within the cytoplasm, a process that
would keep intracellular levels of calcium from rising to toxic levels, although
intestinal calcium transport is not dependent on calbindins, as noted earlier.2
The removal of calcium at the basolateral membrane is mediated by
sodium/calcium exchangers and calcium ATPase. The expression of TRPV6,
calbindin, and PMCA has been shown to be induced by 1,25(OH)2D3. The
mechanism by which 1,25(OH)2D3 regulates phosphate transport is less clear,
and phosphate absorption appears to be less dependent on vitamin D status
than calcium absorption. Low-phosphate diets increase intestinal calcium
transport and the expression of the apical sodium/phosphate co-transporter
NaPi-IIb, which may promote phosphate transport into the epithelial cell, but
this adaptation also occurs in vitamin D receptor (VDR)- and CYP27B1-null
mice.14 The site most sensitive to 1,25(OH)2D3-stimulated calcium transport is
the duodenum, whereas the jejunum is the site most sensitive to 1,25(OH)2D3stimulated phosphate transport.
Renal Reabsorption of Calcium and Phosphate
Just as 1,25(OH)2D3 is the principal regulator of intestinal calcium and
phosphate absorption, PTH and FGF23 are the principal regulators of renal
reabsorption of calcium (PTH) and phosphate (PTH and FGF23), although the
vitamin D metabolites are likely to play some role.15 Given the comparable
proteins in the distal tubule for calcium reabsorption that exist for intestinal
calcium absorption, it is quite surprising that it has been difficult to
demonstrate a direct role for 1,25(OH)2D3 in renal calcium reabsorption in vivo.
PTH reduces the glomerular filtration rate (GFR) and so reduces the filtered load
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Hormonal Regulation of Bone Mineral Homeostasis
of calcium, stimulates active calcium transport in the TALH, and increases
calcium flux into the epithelial cells of the distal tubule through TRPV5 calcium
channels. The calcium-sensing receptor also plays an important role in the renal
handling of calcium by responding to increased calcium with inhibition of
calcium reabsorption in the TALH and promoting diuresis via inhibition of the
water channel aquaporin 2. Control of phosphate reabsorption occurs
primarily in the proximal tubule, and the major regulation is focused on the
expression and function of the sodium/phosphate co-transporter NaPi-IIa. PTH
and FGF23 both suppress NaPi-IIa and so inhibit phosphate reabsorption.
Dietary levels of phosphate have been shown to modulate renal phosphate
reabsorption independent of PTH, but whether phosphate has a direct action
on phosphate reabsorption or whether it works primarily through FGF23 has
not been settled.
Figure 3: Bone Mineral Homeostasis—Mineral Feedback Loops
Gut
+ –
+
Blood
Ca, P
25 OHD
Bone
+ –
+
FGF23
PTH
+
Kidney
–
Urine
Parathyroid
glands
–
–
+
Regulation of Bone Remodeling
The regulation of bone remodeling by PTH, 1,25(OH)2D3, and FGF23 is
complex. The major cells in bone responsible for bone remodeling are the
osteoblasts that form new bone, the osteoclasts that resorb bone, and
the osteocytes that may be the prime environmental sensors that
direct where and how much bone should be formed and resorbed. Although
osteoblasts contain VDR and can be shown to respond to 1,25(OH)2D3, at
least in vitro, studies with mice (and humans) null for or containing
inactivating mutations in the VDR or CYP27B1 suggest that as long as
adequate levels of calcium and phosphate in the blood are maintained, bone
formation is relatively unimpaired in the absence of 1,25(OH)2D3 or its
receptor (VDR).16 This may be a simplistic interpretation, but certainly rickets
can be prevented in such circumstances by providing diets high in calcium,
phosphate, and lactose to enhance non-vitamin-D-dependent calcium and
phosphate absorption. Osteoblasts are not the only cells in which
1,25(OH)2D3 and calcium play complementary roles, and one may interpret
these results to indicate that at least in bone 1,25(OH)2D3 plays a modulating
role to facilitate the actions of calcium, phosphate, and other hormones.
The actions of PTH are no less complex. Continuously high levels of PTH lead
to bone resorption, and in vitro its actions result in decreased osteoblast
proliferation and differentiation. The stimulation of bone resorption can be
understood by the ability of PTH to induce receptor activator of nuclear factor
kappa B ligand (RANKL) (as can 1,25(OH)2D3), a major molecule produced by
osteoblasts, which by interacting with RANK in osteoclasts and their precursors
increases both osteoclast number and activity. PTH also inhibits osteoprotegerin
(OPG), a RANK decoy that blocks RANKL function. Less clear is how PTH
stimulates bone formation.
Recently, two not mutually exclusive possibilities have emerged. PTH has been
found to inhibit sclerostin (SOST) expression in osteocytes.17 The gene product
of SOST is SOST, which is an inhibitor of the wnt pathway. Activation of the
wnt signaling pathway underlies the high-bone-mass phenotype found in
individuals with specific mutations in LRP5, a co-receptor for the wnt receptor
frizzled, rendering it less susceptible to inhibition by SOST and Dkk-1.18 Wnt
signaling can lead to osteoprogenitor proliferation via activation of b-catenin.
Therefore, PTH, by inhibiting the inhibitor, activates the wnt pathway and so
increases osteoblast numbers. A second mechanism involves IGFs. IGF-I (or
IGF-II) stimulates osteoblast proliferation and differentiation and blocks their
apoptosis.19 IGF-I is also required for osteoclast formation and activity.20 PTH
stimulates IGF-I production by osteoblasts. Mice null for IGF-I or its receptor
(IGF-IR) have a markedly blunted response to PTH with respect to bone
US MUSCULOSKELETAL REVIEW
Ca
–
+
P
1,25(OH)2D
Blood levels of calcium (Ca) and phosphate (P) control the secretion of the hormones that
regulate their levels in blood. Ca and P absorption from the intestine is stimulated by
1,25(OH)2D3, but high levels of Ca and P inhibit 1,25 dihydroxyvitamin D (1,25(OH)2D3)
production either directly or by inhibiting parathyroid hormone (PTH) production (by Ca) or
stimulating fibroblast growth factor 23 (FGF23) production (by P). The excretion of Ca by the
kidney is reduced by PTH, whereas the excretion of P is stimulated by both PTH and FGF23. High
levels of 1,25(OH)2D3 and PTH lead to a net loss of bone (with increases in blood levels of Ca
and P), but lower and/or cyclic levels of these hormones increase bone formation.
formation (or osteoclast formation).21 At this point, it is not known whether the
IGF signaling pathway and the wnt signaling pathway overlap in mediating
the anabolic actions of PTH, but it is likely that they do.
Elevated levels of FGF23 as they occur in various genetic and tumor-induced
forms of hypophosphatemic rickets lead to osteomalacia, whereas lack of
circulating FGF23 results in hyperphosphatemia and tumoral calcinosis.22
What is not clear is whether FGF23 has a direct action on bone to
block normal bone formation/mineralization or whether its actions are
indirect via its ability to inhibit 1,25(OH)2D3 production and phosphate
reabsorption by the kidney. DMP1 is a protein almost exclusively produced
by osteocytes and is thought to be involved in the mineralization of bone.
Mutations in DMP1 lead to rickets and osteomalacia with high FGF23
levels,23,24 suggesting that DMP1 may inhibit FGF23 production by bone, but
these findings are also consistent with the possibility that FGF23
reciprocates by stimulating DMP1 production to complete the feedback
loop. This possibility has not been explored.
Conclusions
The calciotropic hormones interact not only among themselves but also with
the minerals they are regulating in their role as regulators of bone mineral
homeostasis. Although numerous target tissues are involved, as are numerous
ions and hormones, the most important are PTH, 1,25(OH)2D3, and FGF23
acting on bone, intestine, and kidney to regulate blood levels of calcium and
phosphate. Regulation entails control of how much comes into the body from
the diet, how much leaves the body through the kidney, and how much is
stored and released from bone. Both feed-forward and feedback mechanisms
are involved. The mechanisms regulating calcium and phosphate flux in one
tissue differ in detail if not in kind from those in other tissues. Different
hormones act on different tissues. Nevertheless, it is quite apparent that the
different hormones, ions, and tissues involved communicate with each other,
sending and receiving clear messages to ensure the precise regulation of these
important minerals. ■
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Gkika D, Hsu YJ, van der Kemp AW, et al., Critical role of the
epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as
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production by human keratinocytes. Kinetics and regulation, J Clin
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By the Same Author
Non-classic Actions of Vitamin D
Bikle D
Role of IGF-I Signaling in Regulating Osteoclastogenesis
Wang Y , Bikle D , et al.
J Clin Endocrinol Metab, 2008 Oct 14 (Epub ahead of print).
J Bone Miner Res, 2006;21(9):1350–58.
Vitamin D receptors (VDRs) are found in most tissues, not just those
participating in the classic actions of vitamin D such as bone, gut, and
kidney. These non-classic tissues are, therefore, potential targets for
the active metabolite of vitamin D, 1,25(OH)2D. Furthermore, many of
these tissues also contain the enzyme CYP27B1, which is capable of
producing 1,25(OH)2D from the circulating form of vitamin D,
25OHD. This review is intended to highlight the actions of
1,25(OH)2D in several of these tissues, but starts with a review of
vitamin D production, metabolism, and molecular mechanism.
Although IGF-I has been clearly identified as an important growth factor in
regulating osteoblast function, information regarding its role in
osteoclastogenesis is limited. Our study was designed to analyze the role of
IGF-I in modulating osteoclastogenesis using IGF-I knockout mice (IGF-I(-/)). Trabecular bone volume (BV/TV), osteoclast number, and morphology of
IGF-I(-/-) or wildtype mice (IGF-I(+/+)) were evaluated in vivo by histological
analysis. Osteoclast precursors from these mice were cultured in the
presence of RANKL and macrophage-colony stimulating factor (M-CSF) or
co-cultured with stromal/osteoblastic cells from either genotype. Osteoclast
formation was assessed by measuring the number of multinucleated
TRACP+ cells and pit formation. The mRNA levels of osteoclast regulation
markers were determined by quantitative RT-PCR. In vivo, IGF-I(-/-) mice
have higher BV/TV and fewer (76% of IGF-I(+/+)) and smaller osteoclasts
with fewer nuclei. In vitro, in the presence of RANKL and M-CSF, osteoclast
number (55% of IGF-I(+/+)) and resorptive area (30% of IGF-I(+/+)) in
osteoclast precursor cultures from IGF-I(-/-) mice were significantly fewer
and smaller than that from the IGF-I(+/+) mice. IGF-I (10ng/ml) increased the
size, number (2.6-fold), and function (resorptive area, 2.7-fold) of
osteoclasts in cultures from IGF-I(+/+) mice, with weaker stimulation in
cultures from IGF-I(-/-) mice. In co-cultures of IGF-I(-/-) osteoblasts with
IGF-I(+/+) osteoclast precursors, or IGF-I(+/+) osteoblasts with IGF-I(-/-)
osteoclast precursors, the number of osteoclasts formed was only 11 and
48%, respectively, of that from co-cultures of IGF-I(+/+) osteoblasts and
IGF-I(+/+) osteoclast precursors. In the long bones from IGF-I(-/-) mice,
mRNA levels of RANKL, RANK, M-CSF, and c-fms were 55, 33, 60, and 35%
of that from IGF-I(+/+) mice, respectively. Our results indicate that IGF-I
regulates osteoclastogenesis by promoting their differentiation. ■
Medline was searched for articles describing actions of 1,25(OH)2D
on parathyroid hormone and insulin secretion, immune responses,
keratinocytes, and cancer. Vitamin D production in the skin provides
an efficient source of vitamin D. Subsequent metabolism to
1,25(OH)2D within non-renal tissues differs from that in the kidney.
Although VDRs mediate the actions of 1,25(OH)2D, regulation of
transcriptional activity is cell-specific. 1,25(OH)2D inhibits PTH
secretion but promotes insulin secretion, inhibits adaptive immunity
but promotes innate immunity, and inhibits cell proliferation but
stimulates their differentiation.
The non-classic actions of vitamin D are cell-specific and provide a
number of potential new clinical applications for 1,25(OH)2D3 and its
analogs. However, the use of vitamin D metabolites and analogs for
these applications remains limited by the classic actions of vitamin D
leading to hypercalcemia and hypercalcuria. ■
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