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5 Vitamin D Maintenance of Skeletal and Vascular Integrity Unrelated to the Attenuation of Secondary Hyperparathyroidism

5 Vitamin D Maintenance of Skeletal and Vascular Integrity Unrelated to the Attenuation of Secondary Hyperparathyroidism

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A.S. Dusso



insufficiency and low VDR in bone cells contributes to the wide range of bone disorders in CKD.

Initial studies in the VDR null mouse suggested that VDR was dispensable for

the ossification process, as non-visible abnormalities in bone mineral density were

observed if there was an adequate supply of calcium and phosphorus by the so

called rescue diet [68]. However, comprehensive studies in the VDR null,

1α-hydroxylase null, and PTH null mice and multiple double knock-out combinations demonstrated calcitriol essential actions for a healthy bone. These include the

induction of osteoblastogenesis, skeletal anabolism and the appropriate coupling of

osteoblastic and osteoclastic activity [69, 70]. Indeed, the calcitriol/VDR complex

regulates the expression of genes that control both bone formation, mineralization

and remodeling (osteopontin, osteocalcin and, importantly, the Wnt receptor LRP5)

as well as osteoclastogenesis and bone resorption genes (RANK ligand and osteoprotegerin) through classical genomic actions (Reviewed in [27]).

In health, the prevalence of bone formation over resorption depends upon the

physiological or supraphysiological concentrations of serum calcitriol. Also, comparison of calcitriol and paricalcitol actions in bone, in mouse and rat CKD models,

have demonstrated that despite differences in osteoclastogenic potency, both compounds similarly maintained bone anabolism [71, 72]. Indeed, not only high calcitriol potently induces RANK ligand (RANKL) but it also suppresses the expression

of its decoy receptor osteoprotegerin (OPG) to amplify resorptive signals. In CKD,

defective calcitriol/VDR induction of osteopontin could not only adversely impact

ossification and remodeling but also osteoclast recruitment to resorb ectopic bone

(reviewed in [27]). Similarly, impaired induction of osteocalcin could negatively

affect bone strength and energy metabolism through osteocalcin-mediated insulin

release [73]. Calcitriol actions in cells of the osteoblastic lineage also depend on

their stage of differentiation being anabolic and anticatabolic in more mature cells,

as demonstrated by overexpression of the VDR in mature osteoblasts in vivo [74].

The conflicts regarding net calcitriol actions in bone may result in part from the

coexistence of all of these distinct cell maturation stages.

The VDR also induces the LRP5 gene, involved in Wnt pathway activation, a

process critical for skeletal development and mineralization. Although LRP5 induction by the VDR appears to occur regardless of calcitriol binding, intracellular calcitriol levels determine cytosolic VDR content, as calcitriol binding protects the

VDR from proteosomal degradation [75].

CKD-induced defects in Wnt signaling in osteocytes and osteoblasts have been

the focus of intensive research due to the progressive accumulation of the Wnt

inhibitors sclerostin and Dkk1 with CKD progression [67] and, more significantly,

because of the strong association between impaired Wnt activity, bone loss and

increased vascular calcification [76].

Importantly, in CKD, impaired Wnt activation in bone occurs before elevations

in serum PTH, as demonstrated in a mouse model of polycystic kidney disease [77].

The early increases in bone sclerostin causing bone loss in these mice could be

prevented with an antibody against TGFβ [78], the most abundant cytokine in bone.

This suggests an early onset of CKD-induced increases in TGFβ signaling for Wnt



3 Molecular Biology of Vitamin D: Genomic and Nongenomic Actions of Vitamin D



63



inhibition. Studies in 7/8 nephrectomized (NX) rats fed either normal or high phosphorus demonstrated similar bone sclerostin levels at week 8 after NX despite

marked differences in serum P, PTH, FGF23 and renal damage between dietary

groups, thus corroborating the independence of this early increase in bone sclerostin

of the severity of SHPT [79]. Furthermore, in both mouse and rat CKD models,

bone sclerostin decreased below the level of sham operated controls as PTH and

FGF23 increased, while elevations in bone levels of several Wnt inhibitors other

than sclerostin, including Dkk1, parallel the progressive loss of bone mass [77–79].

Accordingly, bone biopsies in CKD patients corroborated Wnt inhibition despite the

lower number of osteocytes positive for sclerostin [77]). Undoubtedly, these findings challenge the accuracy of serum sclerostin to reflect the degree of bone Wnt

inhibition or even sclerostin levels in bone. More importantly, they provide a previously unrecognized mechanism for the abnormalities in the vitamin D endocrine

system in CKD to affect the bone-vasculature axis from early CKD stages: Impaired

activation of Wnt signals in bone. Indeed, even disregarding the induction of LRP5

by unliganded VDR, a normal vitamin D status could attenuate the adverse TGFβ/

Smad signaling on bone. In fact, VDR signaling antagonizes a range ofTGFβ/Smaddependent transcriptional activation of profibrotic genes through the recruitment of

VDR to loci on these genes that prevent/attenuate Smad3 binding [80].

Importantly, vitamin D regulation of Wnt signaling is tissue specific. In contrast

to bone, in the kidney and the vasculature, vitamin D inhibits Wnt signals [81, 82]

through VDR binding to β-catenin in the cytosol to prevent its translocation to the

nucleus [38] thereby attenuating the adverse impact on Wnt activation on the progression of renal damage and vascular calcification.

In addition, calcitriol/VDR transactivation of the FGF23 gene in osteocytes and

osteoblasts is an essential pro-survival action, as the dominant role of FGF23 is the

renal elimination of phosphorus to prevent hyperphosphatemia and its pro-aging

consequences. Indeed, the main features of the FGF23-null mouse are hyperphosphatemia, high circulating calcitriol, ectopic calcifications, premature aging, arteriosclerosis, osteoporosis [83], a phenotype that can be rescued by dietary

phosphorus restriction [84–86]. Furthermore, double knockouts of FGF23 and

either the VDR [87] or CYP27B1[88] also rescue the adverse pro-aging features of

the FGF23 null mice by preventing hyperphosphatemia. Since FGF23 suppresses

CYP27B1 and induces CYP24A1 in the kidney [83, 89], it is clear that the capability of FGF23 to simultaneously get rid of excessive phosphorus while tightly preventing elevations in serum calcitriol is essential for its pro-survival effects.

However, although renal mRNA levels for CYP27B1 are reduced, 25(OH)D supplementation to hemodialysis patients can normalize serum calcitriol [90]. However,

the contribution of extrarenal calcitriol production cannot be fully disregarded as

FGF23 increases rather than decrease parathyroid CYP27B1 expression [91].

Similarly, despite the increased CYP24A1 mRNA, serum levels of

24,25-dihydroxyvitamin D in non-supplemented or supplemented patients were

persistently lower than normal [92, 93] Clearly, in advanced CKD, the activity of

either enzyme fails to reflect FGF23 control of the respective genes, that is, the damaged kidney fails to respond to FGF23 tight control of renal calcitriol production.



64



A.S. Dusso



There are several putative VDREs for VDR/RXR binding in the FGF23 promoter. Interestingly, FGF23 gene transactivation by calcitriol decreases from

80-fold to four-fold in the presence of inhibitors of new protein synthesis indicating that osteoblasts’ full response to calcitriol induction of the FGF23 gene is

indirect [37].

The low levels of FGF23 in the VDR null mice and CYP27B1 mice [94] suggest

that impaired induction of FGF23 during vitamin D deficiency could contribute to

accelerate pro-aging features and mortality. Furthermore, although phosphorus,

PTH, calcium and the calcium X phosphorus product are recognized stimulators of

circulating FGF23 levels [95–97], in vitro studies have demonstrated that only calcitriol regulates FGF23 gene transcription [98]. Importantly, calcitriol fails to transactivate the FGF23 gene if high calcitriol and hypophosphatemia occur

simultaneously, as demonstrated in a transgenic mouse with an ablation in the gene

for the phosphorus transporter NPT2a [99]. This supports the prevalent role of phosphorus over calcitriol in the upregulation of FGF23. The COSMOS study has also

reported the optimal range for serum phosphorus associated to the lowest risk of

mortality in CKD-5D patients and the benefits of correcting serum phosphorus to

achieve optimal range [66].

Because FGF23 requires membrane klotho as a co-receptor for its phosphaturic

actions [100], and calcitriol also induces the klotho gene [101], it is clear that the

maintenance of a normal bone-kidney FGF23/klotho axis is crucial for survival. The

next sections examine calcitriol control of renal klotho and its abnormalities in

CKD.



3.6



Vitamin D Induction of Bone FGF23 Production

and Renal Klotho Content to Prevent/Attenuate

Hyperphosphatemia



For decades, the most critical action of the calcitriol/VDR complex in the kidney

has been the induction of CYP24A1 to maintain serum calcitriol within normal

limits by degrading excessive circulating calcitriol and/or 25(OH)D to prevent

hypercalcemia and hyperphosphatemia. Accordingly, CYP24A1 has a 25-fold

higher affinity for calcitriol than for 25(OH)D. Induction of CYP24A1 is a classical

genomic action of the calcitriol/VDR complex mainly on two proximal VDREs on

this gene promoter [27]. The pathophysiological relevance of calcitriol induction of

CYP24A1 in almost every vitamin D responsive tissue was conclusively demonstrated by the severe hypercalcemia and nephrocalcinosis of the CYP24A1 null

mouse [102] and in children and adults with a loss of function mutation of this gene

[103, 104].

At present, calcitriol/VDR induction of the mRNA levels of the longevity gene

α-klotho, and the identification of a VDRE in the human klotho promoter [101]

provide a potential causal link for the epidemiological association between vitamin



3 Molecular Biology of Vitamin D: Genomic and Nongenomic Actions of Vitamin D



65



D deficiency and higher risk of all-cause mortality in the general population, a risk

markedly aggravated in CKD patients. Indeed, while klotho disruption confers a

premature aging like syndrome [7], its overexpression is sufficient to extend lifespan in mice [105].

Klotho is expressed in the kidney, the parathyroid gland and the choroid plexus

[106] where it acts as a high affinity receptor for circulating FGF23. In fact, appropriate levels of renal and parathyroid klotho are required for FGF23 phosphaturic

and PTH suppressive actions, respectively. Therefore, calcitriol induction of renal

klotho should attenuate the pro-aging features of hyperphosphatemia. Accordingly,

progressive reductions of renal klotho in CKD patients stages 3–4 were associated

with an impaired response to FGF23, reduced fractional excretion of phosphate and

with a fourfold higher propensity for abdominal aortic calcification, measured by

the Kaupilla index [107], thus supporting the potentiation of FGF23 protective

actions in cells harboring klotho.

However, klotho also exists in a soluble form, generated by proteolytic cleavage

of the transmembrane klotho, which is found in blood, urine and cerebrospinal fluid

[108, 109]. FGF23-independent endocrine actions of soluble klotho (sklotho)

include the modulation of the activity of membrane channels, co-transporters and

signaling pathways not fully characterized that contribute to its potent survival benefits. Indeed, the systemic administration of recombinant klotho rescues the phenotype of the klotho null mice [110], and the renal and cardiovascular damage

associated to acute or chronic renal injury [111–113]. Therefore, maintenance of

renal and/or circulating klotho has become a priority in nephrology and so was the

need of accurate measurements of sklotho as a biomarker of the severity of CKD

and the risk for cardiovascular mortality.

The demonstration that the specific ablation of renal klotho resulted in an 80 %

reduction in circulating sklotho supported the main contribution of the kidney to

serum sklotho [8]. Furthermore, since the phenotypic features of the mouse with a

renal specific klotho ablation recapitulated all of those in the klotho null mice [8],

serum sklotho was considered a valuable biomarker of renal klotho content and of

mortality risks. Indeed, serum sklotho decreases with age [7], hypertension [110],

and systemic inflammation [114], all recognized determinants of renal damage

and cardiovascular disease. However, the recent report that the kidney is the main

organ for the clearance of circulating klotho into the urine, through a process of

transcytosis through tubular cells [115], raised numerous concerns regarding the

accuracy of circulating sklotho to reflect renal klotho content and its pro-survival

benefits. Indeed, sklotho accumulation in the blood due to an impaired transcytosis by the damage kidney will mask the actual renal klotho reduction. Therefore,

upon improvement of currently available assays for serum klotho, it will be important to establish the optimal range for serum sklotho associated with the lowest

mortality risk in the course of CKD. It will be also important to identify the optimal range for urinary sklotho, as is in the apical site of the renal tubule where

sklotho acts to induce phosphaturia, urinary K excretion and calcium reabsorption

(Reviewed in [116]).



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