Nephrol Dial Transplant (2018) 1–9

doi: 10.1093/ndt/gfy115

Bone, inflammation and the bone marrow niche in chronic

kidney disease: what do we know?

REVIEW
Sandro Mazzaferro1,6, Giuseppe Cianciolo2, Antonio De Pascalis3, Chiara Guglielmo2,
Pablo A. Urena Torres4, Jordi Bover5, Lida Tartaglione1, Marzia Pasquali6 and Gaetano La Manna2
1
Department of Cardiovascular Respiratory Nephrologic Geriatric and Anesthetic Sciences, Sapienza University of Rome, Rome, Italy,
2
Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St Orsola Hospital,
University of Bologna, Bologna, Italy, 3Nephrology, Dialysis and Renal Transplant Unit, Vito Fazzi Hospital, Lecce, Italy, 4Ramsay-Générale de
Santé, Clinique du Landy, Department of Nephrology and Dialysis and Department of Renal Physiology, Necker Hospital, University of Paris
Descartes, Paris, France, 5Fundació Puigvert, Department of Nephrology IIB Sant Pau, RedinRen, Barcelona, Catalonia, Spain and 6Nephrology
Unit, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Rome, Italy

Correspondence and offprint requests to: Sandro Mazzaferro; E-mail: sandro.mazzaferro@uniroma1.it

ABSTRACT clinical entity of chronic kidney disease–mineral and bone dis-

Recent improvements in our understanding of physiology have
altered the way in which bone is perceived: no longer is it con-
sidered as simply the repository of divalent ions, but rather as a
sophisticated endocrine organ with potential extraskeletal
effects. Indeed, a number of pathologic conditions involving
bone in different ways can now be reconsidered from a bone-
centred perspective. For example, in metabolic bone diseases
like osteoporosis (OP) and renal osteodystrophy (ROD), the as-
sociation with a worse cardiovascular outcome can be tenta-
tively explained by the possible derangements of three recently
discovered bone hormones (osteocalcin, fibroblast growth fac-
tor 23 and sclerostin) and a bone-specific enzyme (alkaline
phosphatase). Further, in recent years the close link between
bone and inflammation has been better appreciated and a wide
range of chronic inflammatory states (from rheumatoid arthri-
tis to ageing) are being explored to discover the biochemical
changes that ultimately lead to bone loss and OP. Also, it has
been acknowledged that the concept of the bone–vascular axis
may explain, for example, the relationship between bone metab-
olism and vessel wall diseases like atherosclerosis and arterio-
sclerosis, with potential involvement of a number of cytokines
and metabolic pathways. A very important discovery in bone
physiology is the bone marrow (BM) niche, the functional unit
where stem cells interact, exchanging signals that impact on
their fate as bone-forming cells or immune-competent haema-
topoietic elements. This new element of bone physiology has
been recognized to be dysfunctional in diabetes (so-called dia-
betic mobilopathy), with possible clinical implications. In our
opinion, ROD, the metabolic bone disease of renal patients, will
in the future probably be identified as a cause of BM niche dys-
function. An integrated view of bone, which includes the BM
niche, now seems necessary in order to understand the complex
orders and its cardiovascular burden. Bone is thus becoming a
recurrently considered paradigm for different inter-organ com-
munications that needs to be considered in patients with com-
plex diseases.
Keywords: atherosclerosis, bone marrow niche, chronic kid-
ney disease, CKD-MBD, FGF23, inflammation, PTH, renal
osteodystrophy, vitamin D
INTRODUCTION
The recognition in recent years of the embryonic origin of bone
cells (osteoclasts from haematopoietic stem/progenitor cells or
HSPCs, and osteoblasts from mesenchymal stem cells or MSCs)
and of the hormone-like properties of a number of ‘non-collag-
enous bone proteins’ confers on bone the potential for systemic
extraskeletal effects [1]. In addition, the clinical effects of
chronic inflammation in various systemic diseases has increas-
ingly been recognized. Specifically, the mild chronic increase in
blood and tissues of an ever-growing number of cytokines is as-
sociated with worse clinical outcomes [2]. Another recent dis-
covery is the osteoblastic niche, the functional unit where stem
cells, precursors of both haematopoietic and bone cell lineages
(respectively HSPCs and MSCs), share a common environ-
ment. In this niche, these cells exchange signals that modify
their fate in terms of differentiation towards immune-
competent haematopoietic elements (among which osteoclasts
are now included) and bone-forming cells (i.e. osteoblasts and
osteocytes). There is evidence that HSPCs and MSCs share
functional integrations of potential clinical relevance [3]. The
aim of this review is to highlight the emerging potential links
between bone, chronic inflammation and the bone marrow
(BM) niche, in particular in chronic kidney disease (CKD)

C The
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 patients. These patients are special because they suffer a specific
type of metabolic bone disease and low-grade chronic inflam-
mation that can affect, in still underappreciated ways, the func-
tion of the osteoblastic niche; dysfunction of the latter has
recently been recognized for the first time in diabetes [4].
BONE, INTER-ORGAN COMMUNICATIONS
AND CKD
Until recently, bone was perceived as the repository of ions—
mainly calcium (Ca) and phosphate (P)—whose movement
into and out of bone was regulated by parathyroid hormone
(PTH) and active vitamin D through actions on osteoblasts and
osteoclasts. This view changed with the discovery that osteo-
cytes, previously thought to be inactive, in fact orchestrate oste-
oblast and osteoclast activity, including the synthesis of proteins
with hormonal or hormone-like properties. Accordingly, bone
is now recognized as an endocrine organ [5], and at least three
bone proteins have been claimed to have potential systemic
effects: osteocalcin (OC), fibroblast growth factor 23 (FGF23),
and sclerostin (Sost).
OC, the most abundant non-collagenous bone protein, is
produced by osteoblasts during bone synthesis; however, during
osteoclastic resorption OC is transformed into undercarboxy-
lated OC (UcOC), which is freed into blood. By binding to a G
protein-coupled receptor in beta pancreatic cells, circulating
UcOC affects insulin sensitivity and muscle energy metabolism.
Accordingly, OC is regarded as a biochemical mediator of inter-
organ communication between bone and muscle energy [6].
FGF23, mainly produced by osteocytes, is a completely new
player in the field of so-called CKD–mineral and bone disorders
(CKD-MBD) [7]. By binding to FGF receptors, and in the pres-
ence of a co-receptor, alpha-Klotho, which is mainly produced
in the kidney [8], circulating FGF23 regulates P handling and
vitamin D synthesis in renal tubular cells. The FGF23/Klotho
system is essential for P and vitamin D metabolism and repre-
sents the biochemical substrate of the inter-organ communica-
tion between bone and kidney, useful for better classification of
some rare diseases [9]. Notably, in end-stage renal disease
(ESRD) circulating FGF23 levels increase dramatically as an ex-
treme bone response to the burden of P load and altered catabo-
lism. This strong interaction between P and FGF23 has
widened the spectrum of P toxicity to include, besides second-
ary hyperparathyroidism, cardiovascular disease (similarly to
cholesterol) [10, 11]. In fact, higher quartiles of FGF23 have
been associated with poor cardiovascular outcomes in renal
[12–14] and non-renal patients [15], probably due to a direct,
receptor-mediated effect of FGF23 on myocardiocytes that is
capable of inducing left ventricular hypertrophy and myocar-
dial fibrosis independently of the FGF co-receptor Klotho [16].
Further, Ca deficiency reduces circulating levels of FGF23, thus
decreasing the FGF23-mediated inhibition of 1, 25(OH)2D3,
which would exacerbate hypocalcaemia [17]. FGF23 synthesis
in bone is regulated by a number of bone proteins with either
inhibitory or stimulatory effects [18]. Therefore, FGF23 can
also be regarded as an inter-organ communication factor be-
tween bone and the heart.
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Sost, produced by osteocytes, is a powerful inhibitor of the
canonical Wnt (wingless-type mouse mammary tumour virus
integration site) pathway and, as such, is both an inhibitor of
osteoblasts and osteocytes and a promoter of osteoclast activity
[19]. Indeed, human inactivating mutations of the Sost gene are
associated with sclerosteosis [20], while absence of mechanical
load (e.g. due to inactivity or absence of gravity) increases Sost
expression in bone, promoting bone resorption and osteoporo-
sis (OP) [21]. Also, Sost stimulates FGF23 synthesis, thus exert-
ing indirect effects on mineral metabolism [22]. Importantly,
extraskeletal roles are envisaged, since Sost mRNA expression
has been described [23], although not consistently [24], in calci-
fied aortic valves of haemodialysis patients, while higher circu-
lating levels are invariably associated with aortic valve
calcification [23, 24]. Vessel wall media layer calcification, com-
monly identified as arteriosclerosis, is a typical finding of age-
ing, diabetes and CKD whose pathogenesis is now regarded as a
cell-mediated active process involving osteoblast-like cells de-
rived from vascular smooth muscle cells. Therefore, a modula-
tor of osteoblast activity like Sost could well be involved.
Hypothetically, increased tissue levels of Sost might reflect local
inhibition of the osteoblast-like cell-mediated process of calcifi-
cation or high circulating levels of Sost might be a marker of
low bone turnover (which in turn would favour vascular calcifi-
cations). Thus, the extraskeletal effects of Sost have potential
clinical implications for cardiovascular diseases and represent a
new player in the bone–vascular axis.
Besides UcOC, FGF23 and Sost, which can be regarded as
the principal mediators of the systemic ‘CKD-MBD syndrome’
[25], other non-collagenous bone proteins like bone alkaline
phosphatase [26], the Small Integrin-Binding Ligand, N-linked
Glycoprotein (SIBLING) proteins [18], DKK-1 and activin A
[27] are under investigation to elucidate links between bone dis-
ease, derangements of divalent ion metabolism, and the burden
of mortality and morbidity (in particular cardiovascular) car-
ried by CKD-MBD [25].
In summary, bone is no longer to be viewed as a lifeless
framework for muscle action; rather, it is a sophisticated organ
functionally connected with muscle energy metabolism, with
the kidney and with the cardiovascular system (Figure 1). CKD
deeply disturbs bone physiology (as reflected by changes in cir-
culating biomarkers), impairs its mechanical competence (as
reflected by an increased fracture rate) and contributes to the
complex endocrinopathy now associated with worse cardiovas-
cular outcomes. For this reason, there is growing awareness that
in renal patients it is important to recognize the specific types of
renal osteodystrophy (ROD) through a bone biopsy, which is
not routinely performed although it is minimally invasive and
is considered the diagnostic gold standard [28].
BONE AND INFLAMMATION
The link between bone and inflammation is evidenced in the pro-
cess of bone fracture repair, which is, in fact, a true acute inflam-
matory response of the innate immunity type. At the site of a
fracture, bone cells and inflammatory cells are recruited, with re-
sultant intense crosstalk between HSPC (monocyte–macrophage–
osteoclast) and MSC (pre-osteoblast–osteoblast) derived cells [29].
S. Mazzaferro et al.
 FIGURE 1: UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of
target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabo-
lism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a
role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links.

T lymphocytes (which can stimulate osteoclastogenesis) and B
cells [which can regulate the receptor activator of nuclear factor
jB (RANK)/receptor activator of nuclear factor jB ligand
(RANKL)/osteoprotegerin (OPG) axis] are also involved, with
eventual increases in circulating cytokines [30]. Obviously, this
healing process is the same even in the case of asymptomatic
microfractures, so that pathologic increases in microfractures can
turn into systemic inflammation. Upon reflection, any chronic in-
flammatory state can be expected to affect bone cell activity, as is
illustrated by rheumatoid arthritis (RA), OP and atherosclerosis.
In RA, increases in circulating inflammatory cytokines [tumour
necrosis factor-alpha (TNF-a), interleukin (IL)-17, RANKL] stim-
ulate osteoclast maturation and activity, thereby increasing bone
resorption, while increases in DKK-1 and Sost inhibit bone forma-
tion [31], inducing OP. Ageing, recently regarded as ‘inflammag-
ing’ [32], i.e. a chronic inflammatory condition, is considered to
induce senile OP through similar immunologic mechanisms.
Therefore, the link between bone cells and inflammatory cells is
well established, as is encapsulated in the new term ‘osteoimmu-
nology’ [33]. As for the link with CKD, a recent paper has
highlighted how CKD could be regarded as a model of accelerated
ageing, with resultant bone and cardiovascular disease [34].
Interestingly, according to a recent hypothesis, the link between
bone and inflammation may be of evolutionary value in terrestrial
animals. This hypothesis suggests that acute inflammation induces
a ‘sickness behaviour’ (malaise, fatigue, anorexia, etc.) that, in the
affected animals, is necessary to spare the energy required by the
immune response. This adaptive behaviour relies on a complex in-
tegrated energetic-neuroendocrine-immune response that
includes increased bone resorption to guarantee sufficient
amounts of two vital ions like Ca and P, which a resting animal
would not be able to gather. This scenario offers support for the
importance of the above-mentioned link between bone and en-
ergy. Further, one can envisage that, inasmuch as the healing pro-
cess is incomplete and becomes chronic, it will become
maladaptive and responsible for inflammation-related osteopae-
nia (so-called smoldering inflammation) [35] (Figure 2).
The link between atherosclerosis, inflammation and bone
deserves special consideration. Atherosclerosis is a chronic in-
flammatory process in all of its stages. The effect of atheroscle-
rosis, as an inflammatory disease, on bone metabolism and the
development of OP is suggested by observations confirming
that decreased bone mineral density is a good predictor of car-
diovascular events and coronary disease in postmenopausal
women and men >50 years [36]. Moreover, growing evidence
indicates the existence of a correlation between OP and athero-
sclerosis regardless of age, body mass index and cardiovascular
risk factors [37]. Furthermore, chronic inflammatory processes

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 FIGURE 2: Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a ‘sickness behaviour’ usually
ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia.
contribute to vascular calcification, and the common finding of
simultaneous vascular calcification and OP in individual
patients suggests that local tissue factors govern the regulation
of biomineralization [38]. New terms like ‘calcification paradox’
[39] and ‘osteocardiology’ [40] are being coined to illustrate this
clinical link. Vascular calcification in atherosclerosis is triggered
by the response to injury caused by oxidized low-density lipo-
protein (LDLox). LDLox initiates the inflammatory process,
which is amplified by the exposure of adhesion molecules and
by the secretion of interleukins, C-reactive protein (CRP) and
bone morphogenetic proteins (BMPs) by endothelial cells
and smooth muscle cells. All these processes promote increased
oxidative stress and decreased calcification inhibitors, such as
matrix Glutamic acid (Gla)-protein and osteopontin.
Experimental evidence implies that atherosclerotic inflamma-
tory activity has an interrelationship with osteogenic modula-
tion. When exposed to LDLox, endothelial cells express BMPs.
Additionally, TNF-a and interferon-gamma stimulate the en-
dothelium to express OPG, which is also produced in osteo-
blasts and in smooth muscle cells when stimulated with
proinflammatory interleukins [41]. Hyperproduction of inflam-
matory markers such as CRP, IL-1, IL-6 and TNF-a is directly
related to the severity of atherosclerosis and the stimulation of
osteoclastogenesis [42].
Monocytes and macrophages (after HSPC recruitment from
BM) are the dominant type of atherosclerotic inflammatory cell
infiltrates and represent more than half of all cells at the imme-
diate site of plaque rupture. Furthermore, leakage of cytokines
and leukotrienes from activated macrophages in the atheroscle-
rotic plaque enriches the systemic proinflammatory milieu [43].
Another implicated factor is endothelium-derived nitric oxide
(NO), which is reduced at the site of vascular injury. Indeed,
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NO inhibits platelet adherence and aggregation, suppresses
vasoconstriction, reduces the adherence of leucocytes to the en-
dothelium, and suppresses the proliferation of vascular smooth
muscle cells. Therefore, a reduction in NO activity contributes
to a proinflammatory and prothrombotic milieu.
In CKD, an increase in the inflammatory biomarkers TNF-
a, IL-6, IL-1, CRP and fibrinogen has been reported in the
blood [44]. This increase is caused by several mechanisms, in-
cluding reduced clearance of proinflammatory cytokines, in-
creased local production (e.g. due to the blood–membrane
contact in dialysis patients), pathologic permeability of gut to
toxins (so-called leaky gut syndrome) and induction of macro-
phage activation by metabolic acidosis [45–47]. Monocytes and
macrophages are increased in the peripheral blood of uraemic
patients even when there is no clinical evidence of an active in-
flammatory process or an increase in the peripheral blood of
other inflammatory markers, such as CRP or proinflammatory
cytokines [48]. Further, in CKD the mitochondrial respiratory
system is impaired, which may be both a consequence and a
cause of enhanced oxidative stress. Through elevated produc-
tion of reactive oxygen species (ROS), the damaged mitochon-
dria of uraemic patients may be able to activate the NLRP3
inflammasome, a deregulated biological system newly identified
in CKD-5D patients [49–52]. Increased generation of ROS in
chronic renal failure can damage proteins, lipids and nucleic
acids and consequently influence cell function, inhibit enzy-
matic activities of the cellular respiratory chain and accelerate
progression of CKD [53]. Changes in oxidative and antioxidant
status, which occur from the early stages of CKD, may be exac-
erbated by haemodialysis [54, 55]. Therefore, oxidative stress
and chronic inflammation are both important players in the
mechanisms underlying CKD-related accelerated atherogenesis
S. Mazzaferro et al.
 FIGURE 3: CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-a, RANKL, BMPs, etc.)
and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome)
accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of inter-
leukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying
inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic micro-
inflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia.

and ageing [34]. In turn, accelerated atherogenesis will nega-
tively affect bone metabolism (Figure 3).
THE BM NICHE: WHERE BONE AND MARROW
MEET
Bone is the chest for BM cells and the place where the egress of
stem cells, including those already committed towards some spe-
cific lineages, is orchestrated [56]. The transfer of HSPCs out of the
BM to the circulation requires the integrity of bone microarchitec-
ture, within which is contained the BM functional unit: the niche.
A niche is defined as a specialized microenvironment of the
BM, specific for each cell lineage, that hosts and modulates
HSPC renewal and egress into the bloodstream. Inside the
niche, a complicated network of hormones, soluble mediators
and surface cell receptors regulates the HSPC number, fate and
location [57]. The niche is perivascular and located within the
trabecular bone and is settled by osteoblastic cells, endothelial
cells and perivascular MSCs that interact closely with each other
[57, 58]. The BM niche consists of two major elements. The first
is the osteoblastic niche, where cells of the osteoblastic lineage
are key modulators of HSPCs, keeping them quiescent for the
purposes of maintenance and self-renewal. The second element
is the vascular niche, composed of vascular sinuses, lining endo-
thelial cells, CXCL12-abundant reticular (CAR) cells, sympa-
thetic neurons and HSPCs. Each HSPC evolves inside a
specialized and specific niche [57]. Egress of HSPCs out of the
BM and into the bloodstream is known as ‘mobilization’ and is
coupled with HSPC ‘homing’. Homing is a set of complex path-
ways that modulate the mobilization of HSPCs towards both
peripheral BM niches and peripheral tissues [59].
The niche composition and function ultimately depends on
the activity of the bone cells since most HSPCs are found in the
trabecular bone, suggesting that the function of the niche (mo-
bilization and homing) may also be regulated by factors in-
volved in bone remodelling [57, 58, 60].
A high number of osteoblasts raises the stem cell pool size
and adherence in the niche, whereas an increase in osteoclasts
degrades the niche and promotes the egress of HSPCs [61].
These processes are physiologically carried by the joint effect
of PTH and inflammatory cytokines. PTH plays the role of

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 pivotal director of the niche through activation of PTH/PTHrP
receptors (PPRs), leading to HSPC expansion. Following PPR
activation, osteoblastic cells produce high levels of the Notch
ligand, jagged-1, which elicits an increase in the number of
HSPCs [58, 62, 63]. Furthermore, in osteoblasts PTH upregu-
lates both granulocyte colony-stimulating factor (GCSF), which
in turn regulates the expression of inflammatory cytokines
(IL-6 and IL-11) and CXCL12. CXCL12 is the hinge chemokine
involved in the mobilization and homing processes as its inter-
action with the homing receptor CXCR-4, expressed on many
progenitors, is the most important pathway for retention of
HSPCs within the BM as well as for their mobilization. GCSF
depletes osteoblasts and reduces CXCL12 expression in both
osteoblasts and CAR cells, so promoting mobilization of HSPCs
into the vascular sinuses [57, 58, 64].
No less relevant, within the BM niche, is the role of proin-
flammatory cytokines, which maintain the HSPC pool by
tuning size, cell lineage, distribution and phenotype [65].
Inflammatory cytokines also affect the phenotype of BM mac-
rophages (also called osteal macrophages): this process is
known as macrophage polarization. Osteal macrophages are in-
volved in bone repair and remodelling by regulating the cross-
talk between osteoclasts and osteoblasts [66, 67].
Besides PTH, other factors involved in bone remodelling,
such as FGF23/klotho, Wnt inhibitors, vitamin D, vitamin D re-
ceptor and Ca sensing receptor (CaSR), are able to influence the
activity of the BM niche and the HSPC fate [9, 22, 68–70].
Moreover, MSCs give rise to osteoblasts, and their differentia-
tion is stimulated by 1, 25(OH)2D. In addition to being targets
of 1, 25(OH)2D, MSCs can synthesize it [71, 72]. Normal CaSR
expression on HSPCs is an absolute requirement for their lodg-
ing in the endosteal niche of the BM [73].
Given these tight morphological and functional links, any
pathological condition able to induce an imbalance in bone
remodelling and a derangement in cell signaling may disrupt
both the bone microarchitecture and the BM niche function
and consequently the HSPC traffic [74].
All these findings are new features of the complex scenario
of the bone–vascular axis. In fact, HSPCs and the precursors of
cardiovascular cells may also be resident in the vascular or val-
vular wall or be part of the uninterrupted flow of HSPCs ensur-
ing adequate cell renewal and contributing physiologically to
vascular health [75, 76] (Figure 4).
Several chronic diseases such as obesity, atherosclerosis, diabe-
tes and CKD display a unique proinflammatory milieu that, along
with a cluster of metabolic derangements and oxidative stress fac-
tors, may impair mobilization and homing, thereby inducing
shortage and functional impairment of HSPCs, shifting the pro-
genitor cell phenotype and ultimately influencing pathological
processes such as atherosclerosis and vascular calcification.
Diabetes is characterized by a broad derangement of the BM
niche, with an expanded pool of quiescent HSPCs as well as a re-
duced number of osteoblasts slightly expressing CXCL12 and
unchanged CXCL12 expression in CAR cells, resulting in de-
creased mobilization of haematopoietic stem cells [4]. These
changes are acknowledged to be driven by chronic inflammation,
stimulation of innate immunity receptors, and an increase in
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proinflammatory osteal macrophages [4, 77, 78]. This novel type
of diabetic complication, termed ‘stem cell mobilopathy’, is the
pathway via which diabetes accelerates atherosclerosis; it does this
by inducing a shortage of vascular regenerative cells and by shift-
ing the differentiation of BM progenitor cells to pro-calcific [77].
In CKD patients the uraemic inflammatory burden is en-
hanced by the frequent coexistence of diabetes, atherosclerosis
and ageing [34]. In addition, in CKD patients, inflammation is
triggered by specific pathways related to the CKD-MBD syn-
drome. Besides PTH, FGF23 can directly bind and activate
FGFR4 and calcineurin/NFAT signaling in hepatocytes in the ab-
sence of its classic co-receptor alpha-Klotho, leading to increased
expression and secretion of inflammatory cytokines (Figure 1).
The relationship between FGF23 and inflammation seems to
be bidirectional since inflammation increases FGF23 transcription
in osteocytes. However, whether FGF23 stimulates inflammatory
cytokine expression by other target cells such as adipocytes and
osteoblasts is a matter of discussion [79]. FGF23 may influence
the bone microarchitecture by directly tuning bone remodelling.
FGF23, through a soluble Klotho/MAPK-mediated process in-
volving Dkk1 expression, inhibits the osteoblastic Wnt pathway,
so contributing to bone loss in CKD [69]. Moreover, both human
pre-osteoclasts and mature osteoclasts express FGFR1 at all stages
of differentiation, and FGF23 displays biphasic effects on human
osteoclasts, with inhibition of osteoclast differentiation at the early
stages of maturation and stimulation of activity at later stages [80].
CKD-related inflammation and bone mineral disorders
could affect the complex balance within the BM niche, thus de-
ranging the mobilization and homing of HSPCs and fostering
the development of cell subsets expressing an osteogenic pheno-
type. This latter finding may represent a common thread that
links bone remodelling, the BM niche and vascular calcification
in chronic renal failure.
Cells with an osteogenic phenotype may originate from vas-
cular wall-resident MSCs, transdifferentiated mature or circulat-
ing vascular smooth muscle cells, or circulating calcifying cells
(CCCs) [75, 81]. CCCs comprise several osteogenic cell subsets
that express different but interrelated phenotypes, share a com-
mon origin from BM progenitor cells, and are able to promote
intimal calcification. Regardless of the type of BM progenitor
cell, CCCs are defined by the expression of OC and bone alkaline
phosphatase. Their pool includes circulating (mesenchymal)
osteoprogenitor cells, circulating calcifying endothelial progeni-
tor cells (EPCs) and myeloid calcifying cells (MCCs) [82]. EPCs
have been associated with coronary artery disease, calcific aortic
stenosis, OP, diabetes and ESRD [72, 83–85]. MCCs belong to
the myeloid lineage (monocytes–macrophages) and have been
found to be significantly increased in the presence of either car-
diovascular disease or diabetes. In addition, MCC numbers are
higher in diabetic versus non-diabetic patients regardless of the
coexistence of cardiovascular disease, and they are also increased
in the BM and atherosclerotic plaques [86].
BONE, INFLAMMATION AND THE BM NICHE
IN CKD: FINAL CONSIDERATIONS
The role of BM niche impairment in vascular disease in the set-
ting of diabetes and atherosclerosis has been assessed and such
S. Mazzaferro et al.
 FIGURE 4: The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH,
by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs ‘mobilization’ and ‘homing’
into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are
relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and
microarchitecture, are most likely responsible for BM niche dysfunction.

impairment is also considered to be the first step in the process
leading to the appearance of CCCs. This is undoubtedly the
most intriguing, though still relatively uncharted area in the
multifaceted scenario of the bone–vascular axis. The discovery
of BM niche impairment in vascular disease is particularly im-
portant considering that the derangement of the bone–vascular
axis is amplified by ageing and by CKD, diabetes and athero-
sclerosis, the incidence of which is constantly rising in the gen-
eral population. It is possible to speculate that inflammation is
the shared pathogenetic link, also bearing in mind the possible
coexistence of diabetes, atherosclerosis and CKD, and the po-
tential effects on bone remodelling and thus on BM niche func-
tion. Studies on impairment of the BM niche in CKD are still at
an early stage. This is all the more surprising if we consider the
crucial role that PTH, CaSR, FGF23, vitamin D, inflammatory
cytokines and bone cells are acknowledged to play in regulating
the expansion, mobilization and homing of HSPCs. The inflam-
matory burden and the impairment of bone remodelling inher-
ent to the CKD-MBD syndrome most likely compromise the
renewal of HSPCs and the provision of cell progenitors to vas-
cular tissues, as well as promoting the development of cell sub-
sets that express an osteogenic phenotype and thus probably
affect the process of vascular calcification. Overall, like diabetes,
CKD is a potential cause of BM niche dysfunction or mobilop-
athy and this urgently needs to be appreciated. Indeed, the met-
abolic derangements of mineral metabolism and the chronic
inflammatory burden of renal insufficiency can predictably
affect the function of the BM niche. Similarly, the different types
of ROD (e.g. high- or low-turnover bone disease with resulting
differences in bone cell numbers and activity) most probably
impact the BM niche. Therefore, assessment of BM niche func-
tion in CKD patients could be important for the discovery of
new pathways in the complex metabolic disturbance of uraemia
and its heavy burden of morbidity and mortality.
CONFLICT OF INTEREST STATEMENT
None declared. The results presented in this article have not been
published previously in whole or part, except in abstract format.
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Received: 10.1.2018; Editorial decision: 2.4.2018
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