Vascular calcification and osteoporosis—from clinical observation ...
Vascular calcification and osteoporosis—from clinical observation ...
Vascular calcification and osteoporosis—from clinical observation ...
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256 Osteoporos Int (2007) 18:251–259<br />
receptor <strong>and</strong> interference with insulin <strong>and</strong> IGF-1 signaling<br />
through inhibition of tyrosine phosphorylation, resulting in<br />
increased resistance to insulin <strong>and</strong> IGF-1 signaling.<br />
Mice with targeted deletion of Klotho display a short life<br />
span <strong>and</strong> show many features of premature aging, including<br />
infertility, gonadal <strong>and</strong> thymus atrophy, skin atrophy,<br />
decreased number of Purkinje cells, physical inactivity<br />
<strong>and</strong> pulmonary emphysema [13]. Of note, they also<br />
displayed severe osteoporosis <strong>and</strong> progressive atherosclerosis<br />
with associated medial <strong>calcification</strong>. Both the vascular<br />
<strong>and</strong> skeletal abnormalities in Klotho-deficient mice were<br />
prevented by transgenic overexpression of Klotho [13].<br />
Inhibition of insulin <strong>and</strong> IGF-1 signaling by knockout of<br />
insulin receptor substrate (IRS)-1 is able to rescue Klotho<br />
knockout mice <strong>and</strong> to restore the normal life span [51].<br />
Further studies have indicated that Klotho confers antiapoptotic<br />
activity for endothelial cells [52] <strong>and</strong> protects<br />
against oxidative stress [53]. Further vascular studies of<br />
Klotho indicated that it is required for proper angiogenesis<br />
<strong>and</strong> vasculogenesis, since Klotho-deficient mice displayed<br />
reduced tissue capillary density, impaired angiogenesis <strong>and</strong><br />
decreased endothelium-derived nitric oxide release after<br />
ischemic challenge [54]. Of note, histomorphometric analysis<br />
revealed low-turnover osteopenia in Klotho-deficient mice<br />
with a reduced number of osteoblast progenitors <strong>and</strong> a<br />
reduced osteogenic capacity as determined by matrix nodule<br />
formation [55]. Moreover, Klotho-deficient mice showed<br />
decreased osteoclastogenesis <strong>and</strong> upregulated expression of<br />
osteoprotegerin (OPG), an osteoclastogenesis inhibitor [55].<br />
Thus, the Klotho-deficient mice are a promising murine<br />
model to assess age-related mechanisms in human diseases<br />
[13]. It also shows the essential role of aging <strong>and</strong> the<br />
protein Klotho in the common pathogenesis of osteoporosis<br />
<strong>and</strong> vascular disease.<br />
Osteoprotegerin (OPG)<br />
OPG is a glycoprotein that is abundantly expressed by<br />
various tissues, including the skeleton <strong>and</strong> the vascular<br />
wall. It circulates in serum <strong>and</strong> serves as a decoy receptor<br />
for the tumor necrosis factor (TNF) lig<strong>and</strong> superfamily<br />
members RANKL [56] <strong>and</strong> TNF-related apoptosis-inducing<br />
lig<strong>and</strong> (TRAIL) [57]. RANKL is an essential cytokine for<br />
osteoclast differentiation <strong>and</strong> activation, <strong>and</strong> thus, a<br />
stimulator of bone resorption, while OPG neutralizes<br />
RANKL <strong>and</strong> prevents bone resorption <strong>and</strong> bone loss.<br />
OPG knockout mice show severe bone loss <strong>and</strong> suffer<br />
from multiple osteoporotic fractures at the age of 1 month.<br />
These fractures include the longitudinal bones <strong>and</strong> the<br />
vertebral bodies <strong>and</strong> causes progressive crippling [14]. This<br />
phenotype is characterized by an increased number <strong>and</strong><br />
activity of osteoclasts <strong>and</strong> can be completely rescued by an<br />
OPG transgene [58]. By contrast, mice carrying an OPG<br />
transgene or mice treated with an OPG fusion protein [59]<br />
or RANKL knockout mice [60] have no or fewer<br />
osteoclasts <strong>and</strong> develop osteopetrosis with hepatosplenomegaly<br />
due to extramedullary hematopoiesis.<br />
Surprisingly, the majority of the OPG-deficient mice<br />
developed severe medial <strong>calcification</strong>s of the renal arteries<br />
<strong>and</strong> the aorta that led to aneurysm formation <strong>and</strong> lethal<br />
vessel rupture <strong>and</strong> hemorrhage [14]. The vascular abnormalities<br />
were completely abolished using an OPG transgene<br />
approach, but not following postnatal administration of<br />
OPG protein, suggesting local production is important in<br />
the inhibition of vascular <strong>calcification</strong> [58]. The protective<br />
role of OPG in vascular <strong>calcification</strong> is also underscored by<br />
a rat model of vascular <strong>calcification</strong>, in which treatment<br />
with warfarin, an inhibitor of vitamin K-dependent γ-<br />
carboxylation, or supraphysiologic doses of vitamin D are<br />
used to induce diffuse vascular <strong>calcification</strong> [61]. In these<br />
two models, simultaneous administration of OPG fusion<br />
protein with mineralization-inducing agents prevented<br />
arterial <strong>calcification</strong> [61].<br />
Unifying hypothesis <strong>and</strong> conclusions<br />
Here we propose a unifying hypothesis of vascular<br />
<strong>calcification</strong>, that combines both active <strong>and</strong> passive<br />
mechanisms, aspects of bone metabolism <strong>and</strong> age-related<br />
changes (Fig. 2). Under appropriate conditions, cells either<br />
residing in the vascular wall (smooth muscle cells) or<br />
precursor cells with mesenchymal differentiation potential<br />
(e.g., calcifying vascular cells) acquire osteogenic properties,<br />
which may involve BMP <strong>and</strong> cbfa-1 signaling pathways.<br />
This process is physiologically inhibited by factors<br />
such as Smad6 <strong>and</strong> others. These osteoblast-like cells<br />
deposit bone matrix proteins that subsequently become<br />
mineralized (1). In addition, matrix vesicles <strong>and</strong> apoptotic<br />
bodies from calcifying SMC form the nidus for passive<br />
<strong>calcification</strong>, unless physiological inhibitors are present.<br />
These include fetuin-A, MGP <strong>and</strong> osteopontin (2). In<br />
addition, fetuin-A forms soluble “calciproteins” <strong>and</strong> serves<br />
as an opsonin, thus facilitating phagocytic removal of<br />
mineral precipitates (3). The major protective effect of OPG<br />
on the vascular system seems to be due to its potent<br />
inhibition of RANKL, thus suppressing osteoclastic release<br />
of calcium <strong>and</strong> other minerals from bone (4). Whether OPG<br />
has additional beneficial direct effects on vascular wallresident<br />
cells (by inhibition of TRAIL or RANKL) has not<br />
been shown so far. The link between enhanced bone<br />
resorption <strong>and</strong> vascular <strong>calcification</strong> is further supported<br />
by the findings that other inhibitors of bone resorption<br />
(bisphosphonates, selective osteoclastic inhibitor V-H+<br />
ATPase) have similar effects in a vitamin D-induced vascular<br />
<strong>calcification</strong> model [62, 63]. Aging <strong>and</strong> age-related changes