Review Article Potential of RAS Inhibition to Improve ...downloads.hindawi.com/journals/bmri/2013/932691.pdf · have promising results in ghting bone metabolic disorders associated

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 932691, 6 pageshttp://dx.doi.org/10.1155/2013/932691

Review ArticlePotential of RAS Inhibition to Improve MetabolicBone Disorders

Yoseph Gebru,1,2 Teng-Yue Diao,1,2 Hai Pan,1,2 Emmanuel Mukwaya,1,2 and Yan Zhang1,2,3

1 Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, China2 School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China3Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong

Correspondence should be addressed to Yan Zhang; [email protected]

Received 24 May 2013; Accepted 2 July 2013

Academic Editor: John J. Gildea

Copyright © 2013 Yoseph Gebru et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Metabolic bone disorder is usually caused by abnormalities of minerals and hormones metabolism. Recently, it has been provedby several studies that the renin-angiotensin system (RAS) in local bone tissue is directly involved in bone metabolism. Activationof skeletal RAS plays an important role in bone metabolic disorders. Based on in vitro, in vivo, and clinical studies, this reviewexplains the roles of RAS in bone metabolism and also covers the potential approaches and beneficial effects of RAS inhibition onbone health. Differential strategies for inhibiting RAS can be employed to maintain bone health, which are attributed primarily tothe reduced level of angiotensin II (AngII) and suppressed stimulation of the AngII signaling pathway. The use of renin inhibitors,angiotensin-converting enzyme inhibitors, andAngII receptor blockers either individually or in combination with each other couldhave promising results in fighting bone metabolic disorders associated with other cardiovascular diseases as well as independentbone injuries.

1. Introduction

Metabolic bone disorder is a common pathological mech-anism with genetic components characterized by reducedbone mass and increased risk of fractures [1]. It is usuallycaused mainly by abnormalities of minerals such as calcium,phosphorus, and hormones like vitamin D and parathyroidhormone (PTH). Moreover, there are several physiologicalmechanisms that are able to cause bone disorders throughdifferent molecular pathways including the renin angiotensinsystem (RAS) which will be explained in this paper. It is awell-established finding that the integrity and resistance ofbone depend upon the balance between bone formation byosteoblasts and bone resorption by osteoclasts.Therefore, anybiological mechanism that increases osteoclast number andtheir ability to induce bone absorption or decreases osteoblastnumber and their ability to form bone may trigger bone dis-orders. The RAS has been reported to be among these mech-anisms that play an important role in the pathogenesis andprogression of metabolic bone disease through different ways[2].

The first step of the RAS, namely, the conversion of angi-otensinogen to angiotensin I (AngI) is activated by renin, ahighly selective protease secreted from the juxtaglomerularcells in the kidneys. AngI is then converted to angiotensinII (AngII) by the action of angiotensin-converting enzyme(ACE).The relation between the RAS and bonemetabolism ismainly based on the regulation of AngII on bonemetabolism.Previous studies have reported that AngII significantlyincreased TRAP-positive multinuclear osteoclasts with theupregulation of RANKL expression through extracellularkinase of osteoblast [3]. These effects were abolished withcotreatment by ACE inhibitors or angiotensin type 1 receptorblockers (ARBs). These findings are very helpful in targetingRAS as another strategy to treatmetabolic bone disorders likeosteoporosis.

Several studies have been performed to evaluate thebeneficial effects of some RAS-targeting drugs on the qualityof bone mainly RAS-inhibiting drugs. Drugs that inhibitthe RAS, namely, angiotensin-converting enzyme inhibitors(ACE-I) and angiotensin receptor blockers (ARBs) are gain-ing increasing attention to evaluate their potential to increase

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bone quality and decrease fractures mainly in bone disordersassociated with diabetes. Cross-sectional studies on elderlyChinese populations as well as hypertensive menopausalwomen and a prospective cohort study on older Americanmen showed an association of ACEIs use with higher bonemineral density [4]. Additionally, direct renin inhibitors canalso have more potential for inhibiting the pathway withhigher extent. Recent epidemiological studies have reportedthe benefit of these drugs on increasing bone mass anddecreasing the risk for bone fractures [3]. This paper willreview the possible mechanisms by which RAS is involved inbone metabolic disorder and the in vitro and in vivo studiessupporting the idea that RAS inhibition can improve bonequality and reduce bone fractures.

2. The Relation between the RAS Cascade andBone Metabolism

Because the vascular system plays an important role in boneremodeling, the effect of the RAS on bone metabolism wasconsidered to be related only to the regulation of blood flow.However, recent studies are providing some evidences fora direct relation of the renin-angiotensin system with bonemetabolism. Most of these studies indicate that activation ofthe RAS causes abnormal bone metabolism mainly throughan elevation of osteoclastic bone resorption, by using atransgenic mouse model overproducing human renin andangiotensinogen or an infusion of AngII in ovariectomizedrats [5]. AngII, the dominant effector peptide of the RAS, reg-ulates several cellular mechanisms in a wide variety of tissuesin pathobiological states including bone tissue in associationwith AngII type 1 receptor (AT1) [6]. In a study that examinedthe effect of AngII on the differentiation of rat calvarialosteoblastic cells, it showed that AngII inhibited mRNAexpression of osteocalcin (a protein specifically expressedduring maturation of osteoblastic cells) and decreased theactivity of alkaline phosphatase (a marker of osteoblasticdifferentiation) via its receptor AT1 [7].

2.1. Circulatory System RAS. The differentiation of osteoblastand osteoclasts is primarily controlled by two key mediators,core-binding factor subunit alpha-1 (Cbfa1) and receptoractivator of nuclear factor kappa-B ligand (RANKL), which isregulated by the second messenger, cyclic adenosine mono-phosphate (cAMP) [8]. cAMP is a key intracellular signalingmolecule in controlling bone homeostasis, and its levels inplasma and urine were elevated both in osteoporotic andhypertensive patients who apparently have activated RAS[6]. This indicates that the circulating AngII stimulates anincrease of intracellular cAMP and then activates down-stream signaling pathways which in turn alter Cbfa1 expres-sion [9]. It is thus plausible that AngII alters the expressionof Cbfa1 and subsequently reduces osteoblast number tocause impaired bone formation by activating the cAMPsignaling pathway. Opposite to the role of AngII on Cbfa1, theexpression of RANKL in osteoblasts, amarker for osteoclasticactivation, is significantly increased by AngII [10].

In another study which used a chimeric RAS model oftransgenic THM (Tsukuba hypertensive mouse) expressing

the human renin and human angiotensinogen genes, a recentstudy showed that the activation of RAS induces high turn-over osteoporosis. Here, AngII acted on osteoblasts and notdirectly on osteoclast precursor cells and increased osteo-clastogenesis-supporting cytokines, RANKL, and vascularendothelial growth factor, thereby stimulating the formationof osteoclasts [11]. It has also been suggested that AngII actson bone cells by binding to AT1 receptors on osteoblaststhereby promoting the release of mediators. In addition,circulating AngII may also influence calcium metabolism bydecreasing ionized calcium and increasing parathyroid hor-mone levels [12].This is supported by the evidence that AngIIshows the ability to inhibit the expression of osteocalcin anddecrease the activity of alkaline phosphatase, both of whichare essential for bone matrix synthesis and maturation andregulated by Cbfa1 [13].

2.2. Local Tissue RAS. It has been recognized that local tissueRAS plays an important role in bone metabolism indepen-dent from the systemic involvement of RAS supported by sev-eral evidences. Local tissue-specific RAS has been identifiedto regulate regeneration, cell growth, apoptosis, inflamma-tion, and angiogenesis. It is clear that the RAS is regarded asa local tissue system within bone tissues and bone marrowas the components of the RAS are expressed in osteoblastsand osteoclasts [14]. The association of renin, angiotensin-converting enzyme (ACE) and AngII and its AT1 and AT2receptors with both normal and disturbed haematopoiesiscan be an evidence for the existence of a local bone marrowRAS [15]. The expression of the mRNAs of these majorRAS components of human bone marrow samples has alsobeen quantified by reverse transcription-polymerase chainreaction (RT-PCR) to confirm the presence of the local bonemarrow RAS [6]. The expression of RAS components by ratunfractionated bone marrow cells (BMCs), haematopoietic-lineage BMC, and cultured marrow stromal cells was alsoinvestigated to determine which specific cell types may con-tribute to a local bone marrow RAS [16].

Considering that RAS can be activated in local bonemarrow tissue, these findings lead to a hypothesis and furtherstudy about the role of local RAS on bone metabolism. Ourgroup has demonstrated the mRNA expression of RAS com-ponents in mice tibia for the first time, and this localbone RAS is involved in age-related osteoporosis and renalosteodystrophy induced by acute kidney disease [17, 18].Recently, the involvement of local RAS in the pathologyof bone disease was proved by treating mice with losar-tan, where losartan improved hypertension but exacerbatedosteopenic phenotype [11].Therefore, it can be concluded thatAngII accompanied by its receptors act on bone cells via atissue RAS that regulates osteoclast differentiation and affectbone metabolism [12].

3. RAS Inhibition to Ameliorate BoneMetabolic Disorders

As activation of the RAS stimulates the expression of osteo-clastogenic cytokines in osteoblasts, thereby leading to a highturnover bone disease, it is reasonable to hypothesize that

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blockade of the RAS may reduce these symptoms. It shouldalso be noted that inhibition of the RAS improves bonequality independently of its effect on blood pressure.This wasproved by the cross-talk between AT1 and AT2 receptors ofAngII which will be discussed below. The RAS cascade canbe interrupted at different stages of the pathway and can beused as a strategy to improve bone quality and prevent furtherfractures [19].

The core purpose of RAS inhibition is to decrease theproduction ofAngII thereby reducing the adverse effects of itsactions on bone deterioration.Three critical steps in the RASpathway can be targeted for administering specific inhibitordrugs. The first and rate-limiting step of RAS, namely, theconversion of angiotensinogen to AngI is activated by renin,and renin inhibitors can have a great potential in reducingactions of AngII on bone. Aliskiren is a drug of the secondgeneration of renin inhibitors, and it binds to the S3bp bindingsite of renin essential for its activity thereby inhibiting itsactivity [20].

The other target step for RAS inhibitors on the pathwayis the conversion of AngI to AngII by ACE, in which ACE-inhibitor drugs are employed. The third target for specificblockage is inhibiting the pathway of AngII signaling byantagonizing AT1 which is the main cell surface receptor forAngII as well as blockage of AT2. Blockage of AT1 can beachieved by administering Angiotensin II receptor blockers(ARBs). Moreover, it should be noted that RAS inhibitionand blockage can be achieved through applying specific drugsthat act on particular steps of the cascade or using thesemethods in combination. Renin inhibitors, ACE inhibitors,and ARBs are the most important treatment methods beingapplied currently for in vivo and in vitro, as well as clinicalresearch and treatments.

3.1. In Vitro Studies. Previous in vitro studies have suggestedthat RAS may be involved in the regulation of bone cells,even though it was not known whether molecules involvedin RAS are present in bone in vivo. AngII stimulates DNAand collagen synthesis and decreases alkaline phosphataseactivity on bone cell populations derived from the periosteumof fetal rat calvariae and on human adult bone cells obtainedby collagenase digestion from trabecular bone [21]. It isknown that the receptors of AngII are expressed in cultureosteoclasts and osteoblasts, and AngII is postulated to be ableto act upon the cells involved in bone metabolism [22].

In another previous study, AngII stimulated bone resorp-tion in cocultures of osteoclasts with osteoblastic cells, andother bone cells and this action was inhibited by using ACEinhibitors [7]. But it showed no effect either on osteoclastformation or on bone resorption by isolated osteoclasts onthis study. In bonemarrow-derivedmononuclear cells, AngIIsignificantly increased tartrate-resistant-acid-phosphatase-(TRAP-) positive multinuclear osteoclasts [10]. In addition,AngII significantly induced the expression of receptor acti-vator of NF-𝜅B ligand (RANKL) in osteoblasts, leading tothe activation of osteoclasts, whereas these effects were com-pletely blocked by an AngII type 1 receptor blocker (olmesar-tan) and mitogen-activated protein kinase kinase inhibitors.Therefore, it can be suggested that AngII acts on osteoclasts

through the signals and cellular communication betweenosteoblasts and osteoclasts.

3.2. In Vivo Studies. Recent studies have also demonstratedthe expression of RAS components in osteoblasts and osteo-clasts in vivo [16]. To find out whether in vivo bone cellsare the targets of AngII, recent studies have examined theexpression of AngII receptor proteins, ACE, and renin in thebone of adult mice. It has been shown that ACE, AT1, andAT2 are expressed in osteoclasts and osteoblasts, and reninis expressed neither by osteoclasts nor by osteoblasts but bycells within the bone microenvironment [22].

Studies have shown that excessive activation of RAScauses osteoporosis, mainly through an elevation of osteo-clastic bone resorption, by using a transgenic mouse modeloverproducing human renin and angiotensinogen or an infu-sion of AngII in ovariectomized rats. Several recent in vivostudies have reported that inhibition of the RAS at differentstages have a crucial beneficial effect in combating the adverseeffects of bone mineral disorders. Ovariectomy (OVX) ratmodels have shown a significant increase in osteoclast acti-vation as assessed by the tartrate-resistant acid phosphatase(TRAP) activity in the tibia and a significant decrease inbone density evaluated by dual-energy X-ray absorptiometry.This OVX-induced decrease in bone density and increase inTRAP activity were attenuated by the treatment with an ACEinhibitor, Imidapril [10].

In a recent study, mice lacking the gene encoding themajorAngII receptor isoform,AngII type 1A receptor (AT1a),were studied using micro CT scanning, histomorphometric,and biochemical techniques. Both male and female AT1aknockout mice exhibited an increased trabecular bone vol-ume, trabecular bone number, and connectivity at tibialmetaphysis. Quantitative RT-PCR using RNA isolated fromthe tibia and femur revealed that theRANKL/osteoprotegerin(OPG) ratio was increased [11]. Another study which inves-tigated the effects of AT2 receptor blocker on bone massrevealed that AT2 receptor as well as renin and ACE wereexpressed in bone and that AT2 receptor blocker treat-ment enhanced bone mass through both enhancement ofosteoblastic activity and suppression of osteoclastic activityin vivo [23].Thus, the AT1- andAT2-involvedAngII signalingpathway play important roles in regulating bone metabolism.

However, the efficacy of RAS-targeting drugs is oftencompromised by the reactive renin increase caused by disrup-tion of the renin feedback inhibition, and high renin buildupincreases the risk of AngII-dependent and -independentorgan damage [24, 25]. Therefore, more alternatives shouldbe considered to block renin directly from the beginning andin combination with the other methods. There are no muchstudies about the effect of direct renin inhibitors on bonequality, but it can be suggested that these methods may alsohave similar or better beneficial effects alone or in combi-nation with the other RAS inhibition methods. Aliskiren isactive direct renin inhibitor approved for hypertension treat-ment which has showed a therapeutic potential similar to thatof other antagonists of the RAS [26]. More in vivo studiesmay help to exploit the possibility that RAS blockage usingaliskiren may have better osteoprotective effects.


Angiotensin I

Angiotensinogen

AT1 receptor

ARBs: prevent activationof AT1 receptor signaling

ACEI: prevents formation of AngII

Renin inhibitor: prevents formation of AngI

Angiotensin II

Figure 1: Specific sites for the action of RAS inhibition drugs.

3.3. Clinical Studies. Further evidence for a potential roleof the RAS in bone metabolism as well as the therapeuticeffect of RAS inhibition comes from clinical studies. Severalstudies have compared patients with risk of fractures whohave used ACEI and ARBs with patients at similar risks, butno users of these drugs and a significant difference in BMDwere recorded [27]. Another separate study also reported thatpatients treated with an ACE inhibitor showed an increasedBMD and more importantly reduced fracture risks [28].These results imply that RAS inhibitors that are currentlybeing used to treat cardiovascular diseases such as hyperten-sion could be at the same time used for bone disorders whichare usually associated with other cardiovascular diseases.

To achieve more effective blockage of the RAS, differentclasses of drugs can be used in combination. Aliskiren couldeffectively block the generation of active renin and of down-stream components of the RAS in both nonhypertensive andhypertensive human subjects [25]. In this respect, the directrenin inhibitor differs from the ACE inhibitors and ARBs,which attenuate feedback inhibition of renin synthesis andrelease by AngII, resulting in a reactive rise in plasma reninactivity [25]. This makes it more desirable to conduct furtherresearches on searching molecules that can effectively inhibitrenin production and activity. Additional clinical trials can beperformed to assess the efficacy and side effects of monother-apeutic and in combination of the drugs since Aliskiren hasbeen recorded to induce weight loss in some hypertensivepatients with a mechanism that is not yet understood [29].

4. Action Mechanism of RAS Inhibitors

As discussed above, the osteoprotective benefits of inhibitingthe RAS are attributed primarily to reduced level of AngII andthe activity of its signaling pathway. The overall mechanismby which each type of RAS inhibitor achieves its benefit isdescribed as following (Figure 1).

4.1. Renin Inhibitors. In the past, ACE inhibitors and ARBshave been in use for 15–20 years and have proved beneficialeffect in reducing AngII level and related disorders. However,thesemedications were shown to cause renin elevation which

has deleterious effect suggesting that it is better to block renin[30]. Renin is a circulatory enzyme secreted by the kidneys,and it acts on angiotensinogen. Renin inhibitors bind to theactive site of renin and inhibit its binding to angiotensinogen,which is the rate-determining step of the RAS cascade andconsequently prevent the formation of AngI and AngII [31].Aliskiren is the first-known representative of a new class ofcompletely nonpeptide, orally active, and renin inhibitors andhas been shown to inhibit the production of angiotensin I andII [32]. Aliskiren binds to the S3bp binding site of renin essen-tial for its activity thereby reducing plasma renin activity andsuppressing the formation of both AngI and AngII [31, 33].The efficacy of aliskiren is closely correlated to the fact thatrenin is a highly specific protease with no other substrate thanangiotensinogen and highly species specific [34]. Aliskiren isa nonpeptide, piperidine, designed by molecular modelingof transition-state analogs of angiotensinogen, and it bindswith high affinity to the active site of renin [35]. Even thoughits high molecular weight results in a low bioavailability,the absorbed aliskiren is scarcely metabolized and slowlyexcreted with a consequently long half-life of 24 to 40 hours[36]. Therefore, Aliskiren offers investigating the potential ofblocking the RAS at its rate limiting step.

4.2. ACE Inhibitors. ACE is a bivalent dipeptidyl carboxylmetallopeptidase which cleaves the C-terminal dipeptidefrom AngI and converts it to AngII. ACE inhibitors bindto active site of ACE found in the plasma as well as in thebone tissue and inhibit the action of ACE on AngI. This willdecrease the formation of AngII and alter most of its effectswhich appear to be mediated through the AT1 receptor [37].ACE inhibitors differ in the chemical structure of their activemoieties, in potency, in bioavailability, in plasma half-life,in route of elimination, in their distribution and affinity fortissue-bound ACE, and in whether they are administered asprodrugs. ACE inhibitors may be classified into three groupsaccording to the chemical structure of their active moiety.The first group includes captopril and zofenopril whichare sulfhydryl-containing agents. The ACE inhibitors in thesecond group contain dicarboxylate in their activemoiety andinclude more drugs such as Enalapril, Ramipril, Quinapril,Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril,and Trandolapril. The only drug in the third group is Fosino-pril, and it contains Phosphonate in its structure. The actualmechanism by which ACE inhibitors influence bone mass isnot entirely understood, but it is commonly assumed thatthe therapeutic effect comes from decreased angiotensin IIlevels. However, long term administration of ACE inhibitorswas shown to increase plasma renin level due to the shortfeedback mechanism associated with the decrease in AngII[38]. The other drawback of ACE inhibitors comes from thefact that ACE is a relatively nonspecific enzyme that hassubstrates in addition to angiotensin I, and thus, inhibitionof ACE may result in accumulation of these substrates [39].

4.3. Angiotensin II Receptor Blockers (ARBs). TheangiotensinII receptor blockers (ARBs) represent a newer class of RAS-inhibiting agents which are developed to overcome severaldeficiencies of ACE inhibitors. Their mechanism of action

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differs from that of the ACE inhibitors in several ways.ARBs have advantage over ACE inhibitors in selectivelyinhibiting AngII by competitive antagonism of the AngIIreceptors. These drugs block the activation of AT1 receptorand reduce the adverse effects of activation of the RAS onbone metabolism [39]. Almost all the known clinical effectsincluding its role in metabolic bone disorder of AngII aremediated by AT1 receptor as it has been well documentedexperimentally and clinically [40]. Therefore, blocking thisreceptor will reduce the deteriorating effects of AngII on thebone tissue and the direct effects of the receptor itself on bonemetabolism.

In recent years, numerous orally active, selective AT1receptor antagonists have been synthetized which can effec-tively block AT1 receptor. Six ARB drugs, namely, Losar-tan, Valsartan, Irbesartan, Candesartan, Telmisartan, andEprosartan have been accepted by the US Food and DrugAdministration and can be used in the USA and variousEuropean countries for the treatment of hypertension. Thismay show their approval in blocking the RAS with lessadverse effects compared to ACE inhibitors.

5. Future Developments

In themanagement of patients with bonemetabolic disordersand other cardiovascular diseases, high dose of a single classof RAS inhibitors is often necessary to block the systemcompletely and, hence, to obtain the maximal benefits ofblocking the RAS. This will apparently result in a higherexposure to the side effects of this particular class of drugs.In addition, this class of drugs might be effective in blockinga particular target molecule but stimulates another one. Inthese situations, the combination of the three classes of RASinhibitors discussed above seems to be attractive to improvethe overall blockade of the system.

It has been advocated that the dual blockade approachof ACE inhibitors and ARBs theoretically should resultin improved outcomes in both cardiovascular disease andchronic kidney disease which are usually associated withbone disturbances [41]. Once the better way to effectivelyblock the RAS is established, the actual benefits of RAS inhi-bition on bone quality can be examined more simply. Studiesshould also try to compare which combinations amongRAS inhibitors are more beneficial for bone disorders andfor the other cardiovascular diseases independently. Theprevious studies which mostly try to relate RAS inhibitionwith improvement of bone disorder associated with othercardiovascular diseases should also deduce the effects fromthe perspective of an independent bone disorder. The benefitof RAS inhibition on bone diseases should independently bestudied as bonemetabolism can be altered due to other causesother than hypertension and kidney failures.

In addition, there is an emerging evidence showing theexistence of RAS components in the bonemarrowmicroenvi-ronment [42], and the functional and pharmacological exper-iments have demonstrated that RAS regulates bone marrowstromal cells, and stem cells, thus involving haematopoiesisand tissue regeneration by progenitor cells [42–44]. Whetherthere is a role of bone marrow RAS in bone metabolism and

there are any interactions of the RAS between bone marrowand bone tissue itself still need to be further investigated.

Conflict of Interests

The authors declare that they have no conflict of interests.

Acknowledgments

Thisworkwas sponsored by Innovation Program of ShanghaiMunicipal Education Commission (11ZZ137) and partiallysupported by Hong Kong Scholars Program (XJ2011022) andNational Natural Science Foundation of China (81202894).

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