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Hypertension and Osteoporosis: Common Pathophysiological Mechanisms

Luciana Do Carmo, David G. Harrison

PII: S2590-0935(20)30021-7
DOI: https://doi.org/10.1016/j.medntd.2020.100047
Reference: MEDNTD 100047

To appear in: Medicine in Novel Technology and Devices

Received Date: 10 June 2020

Revised Date: 3 September 2020
Accepted Date: 13 September 2020

Please cite this article as: Carmo LD, Harrison DG, Hypertension and Osteoporosis: Common
Pathophysiological Mechanisms, Medicine in Novel Technology and Devices, https://doi.org/10.1016/
j.medntd.2020.100047.

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Hypertension and Osteoporosis: Common Pathophysiological Mechanisms

Luciana Do Carmo

David G. Harrison

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Division of Clinical Pharmacology and Department of Internal Medicine,

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Vanderbilt University Medical Center
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Address for Correspondence:

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David G. Harrison, MD
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Betty and Jack Bailey Professor of Medicine, Pharmacology and Physiology

Director of Clinical Pharmacology

Room 536, Robinson Research Building

Director, Division of Clinical Pharmacology

2220 Pierce Ave, 536 RRB

Vanderbilt University School of Medicine

Nashville, TN 37232-6602

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 ABSTRACT

Hypertension is a common disease affecting almost one half of adults and is a major cause of

morbiditiy and mortality. Substantial epidemiological data suggest that there is a relationship

between hypertension and osteoporosis although the underlying mechanisms remain poorly

defined. It is now clear that inflammation and immune activation contribute to the end-organ

damage that occurs in hypertension, and that factors in the hypertensive environment, including

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increased sympathetic outflow, cytokines, angiotensin II, oxidative stress and vascular disease

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can affect bone metabolism and the balance between bone generation and resorption. Many of

these events likely contribute to osteoporosis. In this review we will consider these factors and
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discuss potential diagnostic and therapeutic measures that might be implemented to improve
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these diseases.
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Keywords: sympathetic, oxidative stress, colony stimulating factor 1, cytokines, vascular

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dysfunction.
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1. Introduction

According to recent AHA/ACC guidelines, hypertension affects approximately one-half of the adult

population [1]. Arterial hypertension is a prominent cause of death worldwide, and an important risk

factor for chronic kidney disease, atherosclerosis, coronary heart disease and stroke [2]. In the last

fifteen years it has become increasingly apparent that bone marrow-derived cells play a role in

hypertension [3]. For more than 50 years, it has been recognized that in both humans with

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hypertension and in experimental models of this disease, there is a striking lymphocytic and

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monocytic infiltrate in target tissues like the kidney and vascular wall. Factors common to

hypertension, including increased sympathetic outflow, enhanced salt intake, excessive angiotensin
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II and aldosterone (Figure 1), seem to activate immune cells. It is now understood that these cells
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enter target organs like the vasculature and kidney where they release potent mediators like
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cytokines, matrix metalloproteinases and reactive oxygen species, which in turn cause organ
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dysfunction, tissue damage and further blood pressure elevation [4].

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Another common disease is osteoporosis, characterized by reduced bone mass and structural
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deterioration of bone tissue, leading to bone fragility and increased risk of low energy fractures.

Osteoporosis is particularly common in post-menopausal women, and the incidence of bone

fracture in women over the age of 60 is more than twice that of men in the same age group [5].

Interestingly, there appears to be a relationship between hypertension and osteoporosis, particularly

in women. Bone loss is associated with blood pressure in older women [6], and hypertension

increases the incidence of hip fracture in women [7]. Cappuccio et al. measured bone mineral

density 3.5 years apart in 3676 women and found the rate of bone loss over this time was 0.35%

per year in those in the lowest quartile of blood pressure and this was almost doubled in the highest

quartile [6]. Likewise, Afghani and Johnson showed significant inverse relationships between both

systolic and diastolic pressure and bone mineral content in overweight and obese Hispanic women
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[8]. A meta analysis by Li et al of more than 1.4 million subjects indicate that osteoporotic fractures

are 33% higher among those with hypertension than without and that this is true in both Asia and

Europe [9]. Like osteoporosis, hypertension becomes increasingly prevalent with aging, such that by

age 70, 70% of the population is hypertensive. Hypertension is also less prevalent in females before

menopause but becomes more frequent thereafter, again mimicking a pattern observed in

osteoporosis. In this review, we will consider potential mechanistic links between these two

diseases.

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2. Myeloid-derived cells in hypertension:

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2.1. Myeloid cell lineage and role in hypertension: Myeloid cells include granulocytes,
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monocytes, macrophages, mast cells, dendritic cells and megakaryocytes. These are produced

from myeloid precursor cells in primary lymphoid organs, in bone marrow, in the fetal liver during
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embryonic development and as part of adult hematopoiesis [10]. This complex field has been
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reviewed in depth [11], however it is now clear that there are macrophages and likely dendritic
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cells (DCs) that are derived from the embryonic yolk sac and that exist and self renew in
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peripheral tissue, while another population of macrophages and DCs are constantly renewed

from the bone marrow, and in particular from monocytes which become activated upon entering

peripheral tissues.

In the past decade, it has become apparent that bone marrow (BM) derived myeloid cells,

including monocytes, DCs and macrophages contribute to hypertension. A seminal study by

Wenzel et al showed that that selective ablation of lysozyme M-positive (LysM+)

myelomonocytic cells using a diphtheria toxin strategy completely prevented experimental

hypertension caused by the hormone angiotensin-ll [12]. Deletion of monocytes reduced the

vascular dysfunction caused by angiotensin II and prevented the vascular oxidative stress that is

normally observed in hypertension. Wenzel et al found hypertension was associated with a

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striking increase in vascular macrophages and that deletion of monocytes dramatically reduced

the vascular accumulation of these cells. The transmigration of monocytes across the

endothelium into the vascular wall is governed by the interplay of monocyte chemokine 1

(MCP1) its receptor C-C chemokine receptor 2 (CCR2). Ishibashi et al showed that angiotensin

II-induced hypertension causes a marked increase in the expression of CCR2 on monocytes of

mice, and that this was associated with enhanced monocyte migration toward MCP1 in vitro and

vascular accumulation of macrophages [13]. This was prevented in mice lacking CCR2 and by

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bone marrow transplantion of CCR2 deficient cells. These authors also showed that monocytes

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of humans with hypertension had increased CCR2 levels and that this is normalized in subjects
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treated with angiotensin II receptor antagonists. Of note, circulating blood levels of MCP1 are
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also increased in hypertensive humans [14]. These results are in accord with a previous study
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showing that CCR2 deficient mice develop reduced vascular inflammation and hypertension in
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response to angiotensin II infusion [15]. A very similar phenotype was observed by De Ciuceis et

al, in mice lacking the cytokine colony stimulating factor-1, which as discussed below, is critical
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for myeloid cell development [16]. Prevailing evidence indicates that monocytes and
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macrophages in the vessel produce reactive oxygen species, cytokines and matrix

metalloproteinases that alter vascular tone, promote vasoconstriction and modulate vascular

remodeling. In addition to the vasculature, myeloid cells are also recruited into kidneys and the

central nervous system in hypertension. In the kidney, immune cells and the cytokines they

release have been implicated in promoting tissue injury, sodium retention and fibrosis and also

in promoting tissue repair [17]. In the central nervous system neuroinflammation enhances

sympathetic outflow and worsens hypertension [18].

2.2 Dendritic cells: Classical DCs represent a specialized form of myeloid cell that are highly

efficient in taking up foreign proteins, processing these and presenting peptides derived from

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these in the context of major histocompatibility complexes to activate T cells. We have found that

DCs accumulate oxidatively modified proteins in hypertension, and that these modified proteins

seem to act as neoantigens to activate T cells [19]. Adoptive transfer of DCs from hypertensive

mice primes hypertension in recipient mice. Similarly, Lu et al recently showed that mice lacking

the Fms-like tyrosine kinase 3 (Flt3), and that therefore cannot form DCs, exhibit a blunted

hypertensive response to chronic ang II infusion, reduced cardiac hypertrophy and reduced

accumulation of memory T cells in the kidney [20]. FLT3-/- mice also had lower levels of renal

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oxidative stress and reduced mRNA levels of the cytokines TNFα and IL-1β. In a related study,

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this group also deleted the zinc finger protein A20 in DCs [21]. A20 suppresses NFκB signaling,
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and these animals exhibited enhanced hypertension in response to ang II and greater renal T
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cell accumulation. Taken together these studies show that antigen presenting cells like DCs and
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activated macrophages play an important role in hypertension, in part by facilitating engagement

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of the adaptive immune system.

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2.3 Myeloid-derived suppressor cells: Myeloid-derived suppressor cells (MDSCs) represent a

unique subset of myeloid cells that were first characterized in murine tumor models to inhibit
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immune suppression of tumor growth. Shah et al showed that depletion of these cells

augmented hypertension, while adoptive transfer of these cells reduced hypertension [22].

These investigators also showed that hypertension stimulated the immune suppressor function

of MDSCs. Taken together, these various studies have convincingly showed a role of myeloid

cells in the genesis of hypertension.

A summary of the formation and actions of monocytes, macrophages, dendritic cells and

myeloid-derived suppressor cells in hypertension is shown in Figure 2. This figure also illustrates

some of known relationships of these cells to osteoclasts, discussed in section 3.

3. Relationship of osteoclasts to other myeloid cells:

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Relevant to the relationship between hypertension and osteoporosis is the role of osteoclasts.

Osteoclasts are characterized by their multinucleated nature and by expression of tartrate-

resistant acid phosphatase (TRAP), the vitronectin receptor, αvβ3 integrin and the calcitonin

receptor [23]. In parallel with the origin of macrophages and DCs, there appears to be a

population of osteoclasts that develop in the embryo from erythro-myeloid precursor cells and

persist for a period thereafter [24, 25]. In addition, osteoclasts derived from hematopoietic stem

cells seem to be involved in long-term bone maintainance after birth and in adulthood. The

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precise precursor of these adult osteoclasts has not been clearly defined but is clearly myeloid in

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lineage [23]. It is now appreciated that while these cells acquire the capacity to reabsorb bone,
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they maintain several aspects of myeloid cells including cytokine production and antigen
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presentation [26], allowing them to affect immune responses. Another aspect of osteoclast is
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that they are adherent to bone, and their differentiation is enhanced by contact between stromal
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and bone marrow cells which suggested that stromal-derived factors are essential for their

development.
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4. Pivotal role of the Colony Stimulating Factor-1 and its receptor in hypertension and
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osteoporosis:

The colony stimulating factor receptor-1 (CSF-1R) is a tyrosine kinase receptor also known as FMS,

cFMS, MCSF-1R or CD115 [27]. The receptor is present in high levels on monocytes, but is also

present in other hematopoietic stem cells, dendritic cells and macrophages. CSF-1R is activated by

CSF-1 and by IL-34 and is produced primarily by osteoblasts, endothelial cells and activated CD4+

T cells [27]. Signaling through CSF-1R and its activation by CSF-1 play a major role in directing

myeloid development, particular toward monocyte dendritic cell precursors and subsequent cells.

CSF-1 seems to have major roles in cancer, in part by stimulating immunosuppressive

macrophages and myeloid-derived suppressor cells that inhibit the immune response to neoplastic
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cells. A perusal of clinical trials.gov indicates that inhibitors of the CSF-1 receptor and antibodies

against CSF-1 are currently being studied as treatments for colorectal cancer, pancreatic cancer,

leukemia, metastatic solid tumors and T cell lymphomas. High levels of CSF-1 have been observed

in the synovial fluid of patients with rheumatoid arthritis and administration of CSF-1 has been

shown to worsen collagen-induced arthritis in mice.

Mice lacking CSF-1 (Op/Op mice) exhibit severe monocytopenia and congenital osteopetrosis due

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to a severe deficiency of osteoclasts [28]. These mice have extensive skeletal deformities and

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restricted capacity for bone remodeling. When atherosclerosis-prone LDL-receptor deficient mice

are crossed with these animals, the severity of atherosclerosis is dramatically reduced [29]. In
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contrast, transgenic overexpression of CSF-1 leads to a striking phenotype of marked osteoporosis,
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increased trabecular and cortical bone osteoclasts, and increased macrophages in the bone
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marrow, liver and spleen [30]. These CSF-1 overexpressing animals also demonstrate low weight,
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decreased mobility and decreased life span. Macrophages from these animals produce increased

amounts of several cytokines including IL-1α, IL-1β, GM-CSF and IL-17A in response to
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lipopolysaccharide stimulation.
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As mentioned in section 2.1, De Ciuceis et al examined the effect of chronic ang II infusion in op/op

mice [16]. The increase in blood pressure in these animals is only about half that observed in wild-

type littermates or in op/+ heterozygotic mice. Vascular remodeling, characterized by a reduction in

lumen diameter and thickening of the vascular smooth muscle (medial) layer is a uniform

consequence of hypertension, and these changes were reduced in both heterozygotic and

homozygotic op/op and op/+ mice. Hypertension uniformly reduces endothelium-dependent

vasodilatation in wild type mice, and this was prevented in op/op mice. Superoxide production by

the aortas and mesenteric arteries was also reduced in the mice lacking CSF-1. A major source of

superoxide in vessels is the NADPH oxidase, and the increase in vascular NADPH oxidase activity
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caused by ang II infusion was also diminished by loss of CSF-1. Many of these findings are likely

due to a reduction of macrophages, however other inflammatory cells and other consequences of

CSF-1 signaling likely also play a role in the pathogenesis of hypertension. Taken together, these

studies illustrate the roles of CSF-1 and CSF-1R signaling in both hypertension and osteoporosis.

5. Factors linking osteoporosis, hypertension and related cardiovascular diseases:

5.1 Sympathetic tone: A factor uniformly present in hypertension is increased sympathetic outflow.

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Lesions of specific sites in the central nervous system, including the subfornical organ and the

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rostral ventral lateral medulla can prevent many forms of experimental hypertension [31]. Drugs that

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block sympathetic outflow or that block either alpha and beta adrenergic receptors effectively lower
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blood pressure [32, 33]. We have found that hypertension is associated with increased expression

of tyrosine hydroxylase in the bone marrow, reflecting increased sympathetic tone [34]. Likewise,
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there is ample evidence that excessive beta adrenergic stimulation leads to bone loss. As an
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example, Tekada et al showed that the bone loss caused by leptin is mediated by sympathetic
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activation of beta-adrenergic receptors in bone [35]. They showed that mice lacking dopamine beta
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hydroxylase, and that are thus unable to synthesize catecholamines, have high bone mass and that

isoproterenol infusion decreases bone mass, bone formation rate and osteoblast number in either

leptin deficient or wild type mice. Conversely these investigators showed that treatment with

propranolol, a non-selective beta-adrenergic antagonist, increased bone mass in mice and could

prevent bone loss caused by oophorectomy. Recently Khosla et al showed that human bone

contains both β1 and β2 adrenergic receptors and that the selective agonists dobutamine and

salmeterol could elicit downstream signaling in a human osteoblast cell line [36]. These

investigators also found that women taking β1 adrenergic receptor antagonists had higher values of

trabecular number and volume measured by high resolution CT compared to non-users. A separate

group of female subjects were prospectively treated with either a non-selective β receptor
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antagonist or with the β1 receptor blockers nebivolol or atenolol or the non-selective agent

propranolol. β1 blockade also caused a small but significant increase in bone mineral density of the

distal radius and a decline in biomarkers of bone turnover. This study suggests that β1 receptor

activation promotes bone loss and that this can be prevented with commonly used therapeutic

agents. Numerous other studies have supported a role of adrenergic signaling and activity in bone

health [37-39]. While β receptor antagonists are recommended as second-line drugs in the United

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States for treatment of hypertension, it is possible that they might have additional benefits in

patients at increased risk for osteoporosis. The precise kind of β adrenergic receptor antagonist that

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has the greatest benefit in osteoporosis requires further study. In contrast, α adrenergic signaling
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has been implicated in enhancing bone mass [40].
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5.2 Vascular perturbations: Bone is highly vascularized. In addition to the large concentration of

vessels in the periosteum and bone marrow, it has recently been recognized that there is a network
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of transcortical vessels connecting the periosteum to the bone marrow, made up of both arteries
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and veins [41]. While the effect of hypertension on these vessels has not been studied, this disease
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has major effects on vessels elsewhere in the body. These effects include the induction of vascular

remodeling, characterized by thickening of the smooth muscle layer and narrowing of the lumen.

Vascular fibrosis is also common, with deposition of collagen in the adventitia. An extreme

consequence of this remodeling is vascular rarefaction, where smaller arterioles and capillaries

disappear, thus reducing tissue nourishment. Inflammatory cells accumulate in the adventitia and

perivascular fat and can release potent cytokines that have major impact on adjacent cells. The

healthy vascular endothelium produces nitric oxide which promotes vasodilatation, inhibits

inflammation and prevents platelet activation and thrombosis. The enzyme responsible for

endothelial NO production is nitric oxide synthase 3, and mice lacking this enzyme have a profound

reduction in osteoblasts and delayed trabecular bone development [42]. The effects of NO and its
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downstream signaling on bone have been reviewed in depth [43]. Hypertension is associated with a

loss of bioavailable nitric oxide and a loss of its beneficial effects. One explanation for this is that

hypertension is also associated with an increase in the vascular production of reactive oxygen

species, including superoxide and hydrogen peroxide by vascular cells. Superoxide rapidly reacts

with NO, leading to the formation of peroxynitrite, a strong oxidant that has deleterious effects on

proteins, DNA and cellular lipids. Thus, increased production of superoxide and related reactive

oxygen species in vascular cells adjacent to the bone could impair NO signaling.

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Reactive oxygen species produced by the vessel could also have direct effects on bone. In

particular hydrogen peroxide and peroxynitrite are sufficiently long-lived to diffuse from one cell to
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another. A substantial body of literature has implicated oxidant stress in the genesis of osteoporosis
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[44]. Lean et al showed that the induction of osteoclastogenesis in macrophage cell lines in
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response to RANK ligand or TNFα is prevented by overexpressing glutathione peroxidase, a major

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clearance enzyme for peroxides [45]. These investigators also showed that the bone loss following
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oophorectomy can be prevented by administering a membrane targeted form of the hydrogen

peroxide scavenging enzyme catalase. Garret et al provided evidence that superoxide generated
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adjacent to bone could increase osteoclast number and induce bone loss, and that this was

prevented by superoxide dismutase and not by catalase. They also demonstrated that osteoclast

formation in response to parathyroid hormone could be blocked by superoxide dismutase,

suggesting that superoxide in involved in this hormonal response. Bartell et al showed that RANK

ligand induces phosphorylation of the transcription factor FOXO3, and thus decreases its activity in

osteoclast precursors. This reduces cellular levels of catalase and increases hydrogen peroxide

enhancing osteoclast formation [46]. These investigators found that mice with selective deletion of

FOXO3 in myeloid cells exhibit bone loss and this can be reversed by treatment with pegylated

catalase, while overexpression of FOXO3 is associated with increased bone formation. Expression

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of a mitochondrial-targeted catalase prevented osteoclast formation and reduced osteoporosis

following oophorectomy, implicating hydrogen peroxide generated in the mitochondria as a major

modulator of osteoclast formation and bone loss. While this study focused on hydrogen peroxide

generated in the osteoclast precursor, it is possible that hydrogen peroxide generated by adjacent

cells, such as vascular cells in hypertension, could have a similar role.

As discussed above, there is ample evidence that CSF-1 contributes to both hypertension and

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osteoporosis. Interestingly, the vascular endothelium produces CSF-1 at baseline and in response

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to a variety of pathophysiological stimuli. Angiotensin II stimulates transcription of CSF-1 by

endothelial cells via a mechanism involving chromatin remodeling and the AP-1 transcription factors
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c-fos and c-jun [47]. Hematopoietic stem cells are driven to form macrophages when co-cultured
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with hepatic sinusoidal endothelial cells and this is prevented by a CSF-1 inhibitor [48]. Nakano et al
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showed that endothelial cells derived from the synovium of subjects with rheumatoid arthritis
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expressed high levels of CSF-1, and that this stimulates monocyte transmigration and

transformation to osteoclasts [49]. The role of the endothelium as a source of CSF-1 in hypertension
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has not been studied, however factors like angiotensin II and inflammatory cytokines encountered in
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this disease could promote its expression in these cells. These hypothesized interactions are shown

in Figure 3.

5.3 Cytokines: As discussed above, activation of both innate and adaptive immunity contributes to

hypertension, in substantial part because activated immune cells produce cytokines that have

profound effects on the kidney and vasculature. Cytokines that have been implicated include IL-

17A, TNFα, IFNγ, IL-6 and IL-23 [50]. We have shown that effector memory cells accumulate in the

kidney and bone marrow in experimental hypertension, and that these produce copious amounts of

IL-17A and IFNγ. Mice lacking IL-17A have blunted hypertension and do not develop endothelial

dysfunction or vascular stiffening in response to ang II infusion [51, 52]. IL-17A increases activity of
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several renal sodium transporters, in turn leading to salt retention and promoting hypertension [53,

54]. Mice lacking IFNγ are protected against repeated exposures to hypertensive stimuli [55].

Likewise, inhibition of TNFα with etanercept the vascular dysfunction, production of superoxide and

rise in blood pressure caused by chronic ang II infusion [3].

The role of cytokines in bone disease and health has recently been reviewed in depth [56], and it is

clear that many of the cytokines involved in hypertension have major effects on bone. As an

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example, IL-17A stimulates osteoblasts to release Receptor Activator of Nuclear Factor Kappa B

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ligand (RANKL), which stimulates osteoclast-mediated bone resorption by binding to the RANK

receptor expressed by osteoclasts [57]. Treatment with an antibody against IL-17A or silencing the
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IL-17A receptor prevents osteocytic and osteoblastic RANKL production and bone loss in mice [58].
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These findings are interesting in the context of hypertension, because we have shown that effector
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memory T cells accumulate in the bone marrow in hypertensive murine models and can persist for
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long periods even after blood pressure returns to baseline [55]. These cells produce IL-17A and be
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re-actived to re-emerge from the marrow upon re-exposure to the hypertensive stimulus. TNFα

antagonists effectively reduce periarticular bone resorption in rheumatoid arthritis but has varying
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effects in patients with Crohn’s disease that seem dependent on age [59]. A recent meta-analysis

also showed benefit of these agents in preventing bone loss in ankylosing spondylitis [60]. Recently,

Yu et al showed that TNFα promotes the recruitment of T-helper cell 17 (TH17) cells from the gut to

the bone marrow by inducing c-c chemokine ligand 20 (CCL20) in bone marrow stromal cells in

mice during either chronic parathyroid hormone infusion or mice fed a low calcium diet [61]. The

effect of IFNγ is controversial, however most studies suggest that this cytokine inhibits osteoclast

and promote osteoblast formation [62].

5.4 The renin/angiotensin/aldosterone system: While plasma renin activity, which indirectly

reflects a systemic activation of the renin/angiotensin system, is elevated in only about 30% of
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hypertensive humans, inhibitors of this system lower blood pressure in the majority of humans with

hypertension, indicating that angiotensin II plays a role in almost all forms of human hypertension.

Indeed, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are

recommended as first line agents for treatment of hypertension by both the American Heart

Association/American College of Cariology Guidelines and the European Society of Cardiology

(ESC)/European Society of Hypertension (ESH) Guidelines [63]. Angiotensin II not only directly

mediates vasoconstriction and sodium retention by the kidney, but also increases sympathetic

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outflow, promotes oxidative stress and stimulates aldosterone production by acting on angiotensin

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type I receptors in the brain, the kidney and vessel wall.
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Interestingly, experimental evidence indicates that angiotensin II has direct effects on bone. Shimizu
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et al showed that treatment of rabbit bone marrow-derived mononuclear cells in culture with
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angiotensin II dramatically stimulated the formation of osteoclasts, but that this effect was not due to
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a direct effect on osteoclasts, but likely due to stimulation of RANK ligand from osteoblasts [64].

These authors also showed that infusion of a subpressor dose of angiotensin II markedly
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augmented the formation of osteoclasts in female rats that had undergone oophorectomy. This was
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associated in a decline in bone mineral density by more than half that observed in control animals.

The evidence for a role of angiotensin II in humans is not conclusive. A retrospective analysis of the

Women’s Heart Study indicated that there was overall no effect of these agents on bone fracture

[65]. Interestingly, there appeared to be an effect of duration of RAS inhibition. Those treated for

less than 3 years had increased bone fracture, while treatment for longer periods significantly

reduced bone fracture. A recent prospective analysis on the use of RAS inhibitors showed

essentially no benefit or harm on osteoporotic bone fractures [66].

Aldosterone is released from the adrenal cortex in response to either angiotensin II or high levels of

potassium and acts on mineralocorticoid receptors in the collecting duct of the kidney to promote
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sodium retention and potassium secretion. Approximately 20% of humans with resistant

hypertension have primary aldosteronism, a condition caused by autonomous production of

aldosterone by the adrenal gland. The etiology of excess aldosterone production includes unilateral

or bilateral adenomas of the adrenal glands, hyperplasia of the adrenal gland, micronodules, and

microscopic aldosterone-producing cell clusters. Treatment includes surgical resection for unilateral

adenomas, and mineralocorticoid receptor blocking drugs. This subject has been expertly reviewed

recently [67].

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In addition to the kidney, it has also become clear that mineralocorticoid receptors are present in

vascular cells, the brain, and the heart and notably in bone. Beaven et al detected both
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mineralocorticoid and glucocorticoid receptors on osteoblasts, osteocytes, chondrocytes and all
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osteoclasts in samples of neonatal ribs and adult iliac crest biopsies [68]. Petramala et al showed
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that patients with primary aldosteronism had lower serum calcium and higher levels of urinary
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calcium compared to subjects with essential hypertension. Plasma levels of 25-hydroxy vitamin D

were also lower in subjects with primary aldosteronism. These investigators also found higher
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incidences of osteopenia and osteoporosis in these individuals. Rossi et al found a similar pattern of
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urinary and serum calcium and an almost 2-fold increase in serum parathyroid hormone levels in

subjects with primary aldosteronism compared to other hypertensive groups and showed that

treatment with spironolactone or removal of the adenomas normalized these values. These findings

suggest that aldosterone likely has effects not only on bone but possibly the parathyroid glands to

promote bone loss. It is also notable that hyperparathyroidism is commonly associated with

hypertension [69].

5.5 Vitamin D: One of the most attractive explanations for the relationship between hypertension

and osteoporosis is related to the role of vitamin D. Inverse associations between vitamin D levels

and blood pressure have been reported in several cross-sectional studies, and a meta-analysis of
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studies including almost 300,000 subjects showed that the risk ratio for incident hypertension for

individuals with the top third of blood 25-hydroxy vitamin D levels compared to those with the bottom

third was 0.70 [70]. A pooled analysis of five studies indicated that a 10 ng/mL increase in 25-

hydroxy vitamin D levels is associated with a 12% lower risk of hypertension. Li et al knocked out

the vitamin D receptor in mice and found that this increased renin protein levels in the kidney by 4-

fold, more than doubled plasma angiotensin II levels and caused mild hypertension that could be

corrected by treatment with captopril, an inhibitor of angiotensin converting enzyme [71]. In studies

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of cultured cells, the authors showed that vitamin D suppressed activity of the renin gene promoter.

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Similarly, Zhou et al deleted the 1α-hydroxylase gene in mice, which is responsible for synthesis of
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25-hydroxy vitamin D [72]. These mice developed elevated levels of angiotensin II, renin and
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aldosterone. They also had mild hypertension and cardiac hypertrophy and treatment with the
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angiotensin II receptor losartan corrected these abnormalities.

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Despite these compelling epidemiological and experimental studies, there is no evidence that
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vitamin D treatment lowers blood pressure or alters the renin/angiotensin system in humans.

McMullin et al performed a prospective, double blind randomized trial in which obese individuals
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with low vitamin D levels were treated with either placebo or 50,000 IU of ergocalciferol for 8 weeks

[70]. While ergocalciferol treatment significantly increased vitamin D levels, it did not affect plasma

renin activity, angiotensin II levels or blood pressure. It should be noted that the subjects enrolled in

this study were not hypertensive, and therefore an effect in hypertensive subjects could not be

excluded. Pilz et al randomized 200 subjects with arterial hypertension and 25-hydroxy vitamin D

levels below 30 ng/ml to receive either 2,800 IU of vitamin D3 per day or placebo for 8 weeks [73].

Ambulatory 24 hour blood pressure monitoring showed no differences in systolic or diastolic

pressure before and after treatment with either vitamin D or placebo. Similarly, in the Daylight study

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Arora et al found that treatment of patients with pre-hypertension or stage 1 hypertension with 4,000

IU per day of vitamin D had no effect on blood pressure [74].

6 Summary:

In the past decade, there has been an expanding interest in the role of bone marrow derived cells in

the genesis of hypertension. Recent observations also indicate that the bone marrow itself is

affected by hypertension, at least in part through increases in sympathetic tone. While as yet

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unstudied at a basic level, there is also compelling clinical evidence for an association between

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hypertension and osteoporosis. Given the evidence for bone marrow activation in hypertension and

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important role of bone metabolism on the bone marrow niche, additional research is required to
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understand how a common disease like hypertension might affect the bone and in the converse

how bone metabolism might modulate blood pressure. At the minimum, patients with hypertension,
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and particularly older men and post-menopausal women should be screened for osteoporosis and
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treatment initiated when appropriate. It is also possible that therapy for hypertension might be
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modified from existing guidelines in cases associated with bone loss. This interplay of the bone, the
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bone marrow and factors in the hypertensive environment like increased sympathetic outflow,

activation of mineralocorticoid receptors, oxidative stress and inflammation provides an interesting

and compelling field of future study.

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Treiber, G., Drechsler, C., B, O. H., Obermayer-Pietsch, B., Schwetz, V., Aberer, F., Mader, J.,

Scharnagl, H., Meinitzer, A., Lerchbaum, E., Dekker, J. M., Zittermann, A., Marz, W. and

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DAYLIGHT trial, 131 (2015) 254-62. 10.1161/CIRCULATIONAHA.114.011732

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Legends to Figures

Figure 1: Interplay between immune activation, the central nervous system, microbiome, kidney

and vasculature in hypertension. Factors encountered in hypertension, including increased

sympathetic outflow, enhanced salt intake, excessive ang ll and aldosterone and alterations of

microbiome promote immune cell activation. Illustrated here is an interaction of an antigen

presenting cells with a T cell. T cells, macrophages and other myeloid cells enter target organs

like the vasculature and kidney where they release potent mediators like cytokines including

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IL17A, TNFα and IFNγ, which in turn cause organ dysfunction, tissue damage and further blood

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pressure elevation. In the central nervous system neuroinflammation enhances sympathetic
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outflow and worsens hypertension. In the kidney, immune cells and the cytokines they release
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have been implicated in promoting tissue injury, sodium retention, fibrosis and also in promoting
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tissue repair. In the vasculature occurs vasoconstriction, vascular hypertrophy and fibrosis.
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Abbreviations. IL17A: interleukin 17A; TNFα: tumor necrosis factor alpha; IFNγ: interferon

gamma.
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Figure 2: Formation and actions of monocytes, macrophages, dendritic cells and myeloid-

derived suppressor cells in hypertension. Relationship of osteoclasts to other myeloid cells.

Monocytes and DCs are constantly renewed from the bone marrow which become activated

upon entering peripheral tissues. These cells are highly efficient to antigen presentation, they

also release potent mediators like cytokines, MMP, ROS which in turn cause fibrosis. MDSCs

have been shown to lower blood pressure via immunosuppressive functions. Osteoclasts are

produced by fusion of myeloid cells including macrophages. EMP-derived osteoclasts,

macrophages are derived from the embryonic yolk sac and exist and self-renew in peripheral

tissue. Abbreviations. DCs: dendritic cells; MMP: matrix metalloproteinase; ROS: reactive

32
oxygen species; MDSCs: myeloid-derived suppressor cells; CMP: common myeloid progenitor;

EMP: erythro-myeloid progenitors.

Figure 3: Potential affect of vascular disease on bone. Schematically illustrated are periosteal

and transcortical vessels and an expanded view of possible mediators released from the e and

vascular smooth muscle cells. Hypertension is associated with an increase in the vascular

production of reactive oxygen species, including superoxide and hydrogen peroxide by vascular

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cells. Superoxide rapidly reacts with NO, leading to the formation of ONOO⁻, a strong oxidant

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that has deleterious effects on proteins, DNA and cellular lipids. Angiotensin II stimulates
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transcription of CSF-1 by endothelial cells via a mechanism involving chromatin remodeling and
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the AP-1 transcription factors c-fos and c-jun. The activated endothelium also attracts immune
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cells including macrophages and T cells that produce cytokines, ROS and MMPs that affect
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bone. Abbreviations. NO: nitric oxide. ONOO⁻: peroxynitrite. CSF-1: colony stimulating factor 1.

AP-1: activator protein-1.

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Figure 1:

CNS signals
Excess sodium
Aldosterone Vasoconstriction
(altered sympathetic
Vascular hypertrophy
and vagal tone)
and Fibrosis

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IFN
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IL-17A
Hypertension
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TNF
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Sodium
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Asp - Arg - Val - Tyr - Ile - His - Pro - Phe -

Microbiome Volume Retention
Fibrosis
Angiotensin II
Glomerular injury
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 Figure 2:

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 Medicine in
Novel Technology and Devices

Manuscript title

Hypertension and Osteoporosis: Common Pathophysiological Mechanisms

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David G. Harrison

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