Genes & Genomics Online ISSN 2092-9293

https://doi.org/10.1007/s13258-019-00845-3 Print ISSN 1976-9571

REVIEW

Influence of single nucleotide polymorphisms (SNPs) in genetic

susceptibility towards periprosthetic osteolysis
Supriya Jagga1 · Ashish Ranjan Sharma1 · Manojit Bhattacharya1 · Chiranjib Chakraborty1,2 · Sang‑Soo Lee1 

Received: 8 May 2019 / Accepted: 26 June 2019

© The Genetics Society of Korea 2019

Abstract
Wear debris-induced inflammatory osteolysis remains a significant limiting factor for implant replacement surgeries. Hence,
a comprehensive understanding of the complex network of cellular and molecular signals leading to these inflammatory
responses is required. Both macrophages and monocytes have a critical role in the instigation of the inflammatory reaction
to wear debris but differ in the extent to which they induce cytokine expression in patients. Lately, single nucleotide poly-
morphisms (SNPs) have been associated with genetic susceptibility among individual patients with implant failure. Studies
have shown that SNPs in key pro-inflammatory cytokines and their receptors are associated with osteolytic susceptibility.
Likewise, SNPs within several genes involved in the regulation of bone turnover have also been found to be associated with
wear debris induced osteolysis. It is presumed that SNP variance might play a decisive role in the activation and signaling of
macrophages, osteoblasts, chondrocytes, fibroblasts and other cells involved in inflammatory bone loss. Understanding the
extent to which SNPs exist among genes that are responsible for inflammatory bone loss may provide potential targets for
developing future therapeutic interventions. Herein, we attempt to summarize the various susceptible genes with possible
SNP variance that could contribute to the severity of periprosthetic osteolysis in patients with implants.

Keywords  Inflammation · Periprosthetic osteolysis · Single nucleotide polymorphism · Wear debris

Introduction been considered a very reliable rehabilitation technique in

dentistry, with a successful rate of 90% (Adell et al. 1990).
Total joint replacement or dental implant surgeries are some Unfortunately, particulate wear debris, primarily gener-
of the most advanced, efficacious and price effective surgical ated from prosthetic interfaces (bearing surface or modular
interventions in modern medicine (Charnley 1972; Kurcz surface of implants), is implicated as a significant factor in
et al. 2018). Joint replacement surgeries have been success- limiting the survival of implants (Jacobs et al. 1994). Both
ful in providing dramatic pain relief and enhancing joint mechanical and biological factors prompt a cascade of
function for suffering individuals with a variety of end-stage actions leading to the alteration of natural bone homeosta-
degenerative joint diseases. Likewise, dental implants have sis in favor of resorption. Usually, periprosthetic osteolysis
resulting from implant failure is the leading cause and may
Supriya Jagga and Ashish Ranjan Sharma have contributed equally result in loss of bone stock, periprosthetic fractures, loosen-
to this work. ing and subsequent revision of surgery (Lee et al. 2012a, b).
Evidence has shown that wear debris can stimulate
* Chiranjib Chakraborty macrophages to release resorption-mediating inflamma-
drchiranjib@yahoo.com
tory cytokines such as tumor necrosis factor (TNF)α and
* Sang‑Soo Lee interleukin-1 (IL-1). Increased levels of these cytokines
123sslee@gmail.com
have been reported in osteolytic tissues (Jiranek et al. 1993;
1
Institute for Skeletal Aging and Orthopedic Surgery, Hallym Shanbhag et al. 1995; Stea et al. 2000), synovial fluid (Kim
University-Chuncheon Sacred Heart Hospital, Chuncheon‑si, et al. 1998) and regional lymph nodes (Hicks et al. 1996)
Gangwon‑do 24252, Republic of Korea of failed implants. However, recently, variations in osteo-
2
Department of Biotechnology, School of Life Science lytic response to particulate wear debris have been observed
and Biotechnology, Adamas University, Barasat‑Barrackpore among patients (Wilkinson et al. 2005). Various research
Rd, Jagannathpur, Kolkata, West Bengal 700126, India

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studies have also predicted that genetic variation within accepted that mechanical wear of the articulating surface
inflammatory signaling and bone turnover pathways may releases particulate debris. Phagocytosis of this generated
play a prime role in susceptibility to osteolysis (MacInnes debris by monocyte/macrophage lineages and osteoclasts
et al. 2015; Tuan et al. 2008). Macrophage responsiveness causes their activation and often results in enhanced bone
to particulate debris stimulation also varies from individual resorption, leading to bone loss (Fig. 1).
to individual (MacInnes et al. 2015; Matthews et al. 2000). Pro-inflammatory cytokines released from activated
Monocytes obtained from patients who possess susceptibil- immune cells, macrophages and osteoclasts are regarded
ity to osteolysis display greater inducible cytokine responses as initiators and perpetrators for the initial onset of oste-
to prosthesis wear debris compared to patients without this olysis. Reports have demonstrated induced production of
susceptibility (Gordon et al. 2010a, b). pro-inflammatory cytokines in wear particle-stimulated
Variable susceptibility to osteolysis observed among macrophage lineage cells (Nakashima et al. 1999; Rakshit
patients is still mysterious and is assumed to be influenced et al. 2006) and murine models of osteolysis (Millett et al.
by genetic factors. Recently, numerous pro-inflammatory 2002; Warme et al. 2004). Enhanced release of inflamma-
cytokines associated with osteolysis susceptibility have tory cytokines like IL-1, IL-6, and TNFα can upregulate
been shown to possess SNPs (Gallo et al. 2009; Gordon the inflammatory response to wear particles (Koulouvaris
et al. 2008; Wilkinson et al. 2003). A SNP is described as et al. 2008; Nich and Goodman 2014). During the osteo-
an alteration of single nucleotide in the DNA sequence and lytic process, aseptic loosening is characteristically accom-
is the most typical type of genetic variant. It is assumed that panied by the formation of a fibrous membrane at the
the human genome contains approximately 10 million com- interface around the bone-implant interface. Histological
mon SNPs (Mooney 2005). Within a given population, DNA analysis of this membrane revealed a synovial-like fibro-
sequences may be identical up to 99.5% between individuals vascular tissue enclosing macrophages, fibroblasts and for-
(Sherry et al. 2001). However, variability within the codon eign body oversized cells (Noordin and Masri 2012). Mac-
does occur and gives rise to phenotypic variability within rophages and fibroblasts are the predominant driving force
a single population. These variants appear approximately behind osteolysis. These cells mediate signals through
after every 1000 nucleotide base pairs throughout the entire secretion of various pro-inflammatory cytokines (includ-
genome. Specifically, whenever a variation occurs in > 1% ing the IL, vascular IL-6, IL-2, TNFα, and receptor activa-
of the community, it is termed a polymorphism (Gordon tor of nuclear factor-κB (RANK)) following either phago-
et al. 2008). An individual’s specific risk factors for com- cytosis of the particles or surface attachment (Chakraborty
mon diseases are thought to be influenced by a sum of many and Doss 2013; Goldring et al. 1986; Sharma et al. 2013).
genetic variations, where each element potentially causes a Even foreign bodies can directly affect the phagocytic cells
small change in biological function and consequently subtle by inducing apoptosis or cell death (Pioletti et al. 1999;
phenotype, accounting for the varied response among popu- Wang et al. 2004). Several studies have also demonstrated
lations of a disease state. that direct exposure of particulate wear debris or cytokines
In the context of distribution level and function of SNPs, for macrophages can influence the osteogenic differentia-
there are significant areas to be considered in current bone tion process, affecting bone formation (Lee et al. 2011,
biology research. In the current review, we have tried to 2012a, b; Nam et al. 2017). In response to the stimuli from
highlight how SNPs can affect mechanisms of implant- the secreted cytokines in the osteolytic microenvironment,
induced osteolysis and to identify functional variants con- osteoblasts can affect the osteoclastogenesis indirectly by
cerning how downstream molecular effects can be classified secreting M-CSF and RANK ligand (RANKL) (Suda et al.
to relate the candidate genes to their products. 1997). However, still a complete understanding of the bio-
logical processes through which wear particles induce an
inflammatory response or affect the osteogenic activity
Biological aspects of periprosthetic continues to elude the scientific community.
osteolysis Moreover, it remains unclear what clinical contribution
this possible mechanism makes during the development of
Osteolysis is an active biological event that results in wear debris mediated periprosthetic osteolysis (Lee et al.
the loss of bone mass as a direct response to activation 2012a, b). It is assumed that early relocation of the femoral
of monocyte/macrophage lineage-mediated proteins by component might help to predict initial and mid-term pros-
biologically active particles. Aseptic loosening is closely thesis failure. This relocation may cause tissue instabil-
associated with osteolysis, which is also a dynamic pro- ity, locally elevated fluid pressures, which might, in turn,
cess of bone destruction and loss due to a cellular-medi- results in osteolysis (Aspenberg and van der Vis 1998a, b).
ated response (Archibeck et al. 2001). It is commonly

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Fig. 1  Schematic representation of macrophage activation: in an early response to wear debris from implants, macrophages release inflammatory
cytokines either of the two pathways: (1) phagocytosis mediated inflammasome pathway or (2) receptor mediated systematic pathway

Cellular response during periprosthetic expressed in an osteolytic membrane derived from patients

osteolysis with failing prostheses. Bone turnover is tightly controlled
by a balanced equilibrium between osteoblasts and osteo-
Periprosthetic osteolysis arises as a result of cell-mediated clasts that is regulated by the interaction between cytokine
adverse inflammatory immune responses to the wear debris and RANK signaling pathways (Fig. 1), regulators of both
materials shed from the implant surface. Several investiga- inflammation and bone remodeling (Caicedo et al. 2009;
tors have already shown that particulate debris from pros- Wilkinson et al. 2003).
thetic materials after phagocytosis, with or without carrier Patients may vary in their osteolytic response to various
proteins, initiates inflammatory signaling through pattern particulate wear debris generated from different types of
recognition receptors (PRR), including nucleotide-binding prostheses. Cellular macrophages respond to a particulate
oligomerization, domain(NOD)like receptors (NLRs), encounter, but in vitro effects can vary between individu-
C-type lectin receptors (CLRs) and toll-like receptors als. Likewise, monocytes that are derived from patients with
(TLRs) (Gallo et al. 2002; Nich et al. 2013). These receptors a high vulnerability to osteolysis shows greater inducible
play pivotal roles in inflammatory cellular signaling (Fig. 2). cytokine responses to titanium particles compared to those
Other surface receptors that have been reported to induce obtained from patients without this susceptibility (Lee et al.
particle-induced activation of macrophages are CD11b and 2012a, b; Skol et al. 2006; Tuan et al. 2008). Susceptibil-
CD14. The NLRs and TLRs are presumed to play a vital ity to osteolysis varies with patient gender and age, being
role in the inflammasome complex of proteins that sense and more frequent in younger male patients. Candidate gene
initiate pro-inflammatory responses to threats or pathogen- studies have shown that SNPs within several pro-inflamma-
associated molecular patterns within cells (MacInnes et al. tory cytokines are associated with osteolysis susceptibility.
2015; St Pierre et al. 2010). Furthermore, these PRRs are Similarly, variations within several genes involved in the

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Fig. 2  Inflammatory cascade induced by wear debris in periprosthetic tissue produce inflammatory cytokines and proteolytic enzymes such
osteolysis: in implant induced osteolysis, wear debris interact with as (IL)-1α and β, IL-2, IL-6, IL-11, macrophage colony stimulating
various kinds of cells including fibroblast, osteoblast, multinucleated factor (M-CSF) etc. Inflammatory factors further contribute toward
macrophages and osteoclast either directly or indirectly. Once acti- the activation of RANKL/RANK ligand-receptor complex to stimu-
vated macrophages, osteoblast and fibroblasts cells in granulomatous late the process of osteoclastogenesis

regulation of bone turnover are also related with osteolysis precipitating factors and regulatory factors governing this
susceptibility (Kubistova et al. 2006). So far, these stud- cascade (Proff and Romer 2009). Recently, genome-wide
ies have paid attention to specific candidate variants within correlation researches have led to the identification of a
genes that are also known to govern inflammatory responses new dimension in osteolysis, namely genetic polymorphism
or bone turnover, and thus have not explored for other prob- (Javor et al. 2007). Genomics and molecular pathway studies
able modifications within or adjacent to different candidate could provide the knowledge whether the basic alteration of
genes (Table 1) (De Luca et al. 2006). genes or variations among them involved in wear mediated
osteolysis. Even the genes that undergo modulation post-sur-
gery, when the process of osteolysis is initiated in patients,
Genetic basis of periprosthetic osteolysis remains relatively unexplored and might differ from the ones
that are associated with susceptibility. Numerous investiga-
Periprosthetic osteolysis is an active biological cascade that tors have explored the association between genetic variation
occurs in response to particulate wear debris. Several stud- within probable genes and susceptibility to periprosthetic
ies have reviewed the process from varying perspectives, osteolysis. The first identified association was within the
but there is no current consensus on the precise mechanism, promoter region of the gene expressing TNFα (Wilkinson

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Table 1  Single nucleotide variant genes responsible for osteolysis. (Source: http://www.ncbi.nlm.nih.gov/snp/)

Genes SNP number (NCBI) Alleles SNP position in References
chromosome

Osteoprotegerin (OPG) rs2073617 G/A Chromosome 8 Zhou and Zhao (2016)

rs2073618 G/C Chromosome 8 Nava-Valdivia et al. (2017)
rs3102735 C/T Chromosome 8 Gordon et al. (2010b)
rs6993813 C/T Chromosome 8 Choe et al. (2012)
rs6469804 A/G Chromosome 8
Alkaline phosphatase (ALP) rs871132 G/A Chromosome 1 Lazáry et al. (2008)
rs1256341 G/A
rs3738099 G/A
rs10914367 G/A
Fibroblast growth factor receptor-1 (FGFR1) rs13317 C/T Chromosome 8 Xu et al. (2010)
rs3925 G/A
rs2280846 G/A
rs6996321 G/A
rs7825208 G/A
rs12677355 C/T
Matrix metalloproteinase-1 (MMP1) rs5854 C/T Chromosome 11 Malik et al. (2007), Ye (2000)
rs3167647 C/T
rs17293849 C/T
Tissue inhibitor of metalloproteases-2 (TIMP2) rs1384364 C/T Chromosome 17 Malik et al. (2006)
rs931227 G/A
rs9894295 G/A
rs9900972 G/A
rs4796812 C/T
rs4789939 G/A
rs8066116 C/T
Interleukin 6 (IL-6) rs1800797 A/G Chromosome 7 Gordon et al. (2010a, b)
Receptor activator of nuclear factor kappa-B ligand (RANKL) rs9594738 C/T Chromosome 13 Styrkarsdottir et al. (2008)
rs9594759 C/T Chromosome 13
Stimulatory G-protein alpha subunit (GNAS1) – T/C Chromosome 20 Bachmann et al. (2008)
Secreted Frizzled-Related Protein-3 (sFRP3) rs288326 C/T Chromosome 2 Gordon et al. (2007)
rs7775 C/G
B cell lymphoma 2 (BLC2) rs2279115 C/A Chromosome 18 Stelmach et al. (2016)
Toll/interleukin receptor domain containing adaptor protein rs8177375 A/G Chromosome 11 Song et al. (2010)
(TIRAP)

et al. 2003). Till date, several associations between SNPs implant induced osteolysis (Landgraeber et al. 2014). Ear-
and bone turnover pathways and inflammatory cytokines lier investigations depended on measuring the levels of
have been reported (Table 1) (Bachmann et al. 2008; Gallo selected proteins in these fibrous tissues in addition to the
et al. 2009; Gordon et al. 2007, 2008). Analysis of SNPs expression levels of related genes. These candidate gene
among the bone turnover pathways as well as in inflamma- studies either involved hypothesis based on selected genes
tory processes has proposed various key molecules that can or a group of pathway-related genes about the susceptibil-
be linked to the susceptibility to wear particle-induced oste- ity to periprosthetic osteolysis. However, such a selective
olysis like IL-1, matrix metalloproteinases (MMPs), RANK, approach has been unsuccessful thus far in identifying the
RANKL, etc. key molecular drivers of osteolysis. Henceforth, the over-
Based on previous experimental models, the granu- all illustrative focus should be to use the genome-wide
lomatous implant tissues, adjacent to the prosthetic itself, gene expression of SNPs to explain the molecular profiles
hold the key to understanding the pathophysiology of of patients suffering from wear debris induced osteolysis.

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Role of SNPs in osteoprotegerin (OPG), RANK and consequently the level of OPG protein induced, and the
and RANKL during periprosthetic osteolysis RANK SNPs may affect the function of the protein product
(Wuyts et al. 2001). There is a strong association between
Osteoclast-released pro-inflammatory cytokines may mod- single allele variation and osteolysis as a reason of asep-
ulate the activation of various kinds of cell types in the tic and septic failure. Both types of failure likely have such
periprosthetic region, including osteoblasts. Osteoclasts an association because, while the initial stimuli are differ-
can join forces with osteoblasts, resulting in coupled bone ent, the clinical phenotype is similar concerning the nature
remodeling and regulation of bone resorption (Childs et al. and extent of bone loss (Haynes et al. 2001). In the case
2002). Stimulated osteoblast activates monocyte/mac- of dental implants, an association analysis with allelotypes
rophage cell lineage by activating RANK through RANKL demonstrated that SNPs recognized in the RANK/RANKL/
and macrophage colony-stimulating factor (M-CSF) (Boyle OPG genes have no significant relationship with aggressive
et al. 2003). Together, RANKL and M-CSF induce expres- periodontitis in the Japanese population (Soedarsono et al.
sion of genes needed for the growth and maturation of 2006). Another study analyzed the association of OPG gene
polykaryon osteoclasts and initiates their bone resorptive polymorphism to peri-implantitis in Chinese Han popula-
function. The upregulation of periprosthetic bone resorption tions (Zhou and Zhao 2016). It was observed, whether OPG
leads to a loss of integrity of the prosthesis-host construct promoter and intron polymorphism loci T950C (rs2073617)
and subsequent aseptic loosening of the implants. Activated and G1181C (rs2073618) are related to the susceptibility of
mature macrophages also release MMPs that directly destroy peri-implantitis. The study concluded that OPG rs2073618
the demineralized collagen matrix (Aspenberg and van der polymorphism may be associated with the probability of
Vis 1998a, b; Tuan et al. 2008). Fibroblasts are the most peri-implantitis. However, rs2073617 was found not related.
common type of cell type present in the loosening mem- Generally, the genetic susceptibility in the failure of dental
brane part and play a crucial role in the pathogenesis of implant has been confined to candidate genes and population
osteolysis, producing a fibrous collagenous matrix that sur- association analysis.
rounds the prosthesis. Also, fibroblasts release RANKL, and The biological activity of OPG are antagonistic to
IL-6 induces osteoclastogenesis, enhancing the formation of RANKL, and OPG acts as a decoy molecule. The ratio of
multinucleated giant cells. RANKL to OPG is responsible for osteoclast survival, dif-
Along with upregulation of the osteoclast response, par- ferentiation, and movement. Hence, in the future, it will be
ticulate wear debris impedes the differentiation process of exciting to analyse the consequence of polymorphisms in the
mesenchymal stem cells into mature osteoblast and reduces RANKL gene and equate OPG/RANKL/RANK haplotypes to
the synthetic activity of mature osteoblasts for bone forma- attain a comprehensive picture of the impact of nucleotide
tion, altering the balance in favor of net bone loss (Clo- variation in the whole of this genetic system.
hisy 2003). In parallel, the OPG/RANK/RANKL signaling
pathway is implicated in the biological cascade of events Role of SNP in MMP1 during periprosthetic
instigated by particulate wear debris and bacterial infection, osteolysis
causing periprosthetic bone loss around implants (Boyce
and Xing 2008). Individual behavior to these inflammatory MMPs constitute a family of more than 20 homologous
stimuli may be influenced by genetic variation caused by proteolytic enzymes, having the ability to degrade almost
SNPs (Malik et al. 2006). The OPG/RANK/RANKL cas- all constituents of the extracellular matrix in tissues. The
cade directly participates in the pathogenesis of osteolysis. proteolytic activity of MMPs is controlled by activation
This system is assumed to be fundamental to the mecha- of their precursor zymogens and by inhibitory activity of
nism of bone loss (Jones et al. 2002). Molecular studies have endogenous inhibitors like α-2-macroglobulins and tissue
examined the promoter and the exons surrounding intron inhibitors of metalloproteinases (TIMPs) (Nagase and Brew
sequences of the OPG gene as well of RANK for SNPs. 2002).
Variants among TNFRSF11A (RANK) and TNFRSF11B MMP1 is a member of the mammalian extracellular neu-
(OPG) demonstrate a close association with susceptibility to tral metalloproteinases, having the ability to degrade matrix
osteolysis, and function similarly to these genes in modulat- proteins and mediate connective tissue remodeling. It has
ing osteoclast differentiation and activation. The functional the ability to break down interstitial collagens I, II and III.
effect of these variants is ambiguous, most of them are in MMP1 are also involved in the hydrolysis of gelatin and
non-coding areas of the gene. However, they might act as type IV collagen (chief structural component of the base-
markers for non-synonymous SNPs or control transcrip- ment membrane), along with elastin, laminin, fibronectin
tion and translation by effecting mRNA stability, splicing, and fibrillin (Jung et al. 1997). Recently, a number of other
or binding of miRNAs (MacInnes et al. 2015). However, substrates have also been recognized for MMP1, such as
SNPs in the OPG promoter could influence transcription, growth factor precursors, cytokines (e.g., pro-TNFα) and

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binding proteins (McCawley and Matrisian 2001). Usually, roles. Therefore, the association that is between a specific
MMP1 is secreted in low quantity, but expression can be polymorphic form of MMP1 and implant rejection does
induced by growth factors, phorbol esters and inflammatory not mean that the particular SNP is related with increased
cytokines (Kerkela et al. 2001). MMP1 activity; in fact, the reverse might be true (Ma et al.
SNPs in the MMP1 gene has been found associated with 2000; Malik et al. 2007).
enhanced transcription factor synthesis, metastasis, and inva- As discussed earlier, genetic polymorphisms have a
siveness of several types of cancers, cartilage obliteration in significant role in dental implant osteolysis concerning
arthritis and untimely rupture of fetal membranes (Ye 2000). the development of extracellular matrix by morphological
Researchers have analyzed periprosthetic tissues from some differences between material surfaces, signifying that the
patients to study the mRNA expression pattern, and various extracellular behavior can be affected by the implant surface.
kind of MMP1 SNPs have been identified (Del Buono et al. In postmenopausal women, SNP in the promoter region of
2012). Malik et al. demonstrated that SNP in the promoter MMP1 has been found associated with the decreased bone
region of MMP1 is related to the early revision of total hip mineral density of the distal radius, implicating the direct
replacement surgeries (Malik et al. 2007). Another study by role of MMP1 polymorphism in extracellular matrix mainte-
Godoy-Santos et al. also analyzed and concluded that SNPs nance (Yamada et al. 2002). Moreover, MMPs represent the
in the promoter region of MMP1 is associated with aseptic main class of enzymes accountable for extracellular matrix
loosening of implants as compared with controls (deficient metabolism. Therefore, MMP-1 as avital mediator of the
in SNP) (Godoy-Santos et al. 2009). degradation of collagen, which is copious in connective tis-
Inspection of the MMP genes that map to this region sue and bone matrix, has a crucial role in implant-induced
revealed several other disease candidates. Previously, MMP1 osteolysis and SNPs within its promoters should be regarded
was believed to be involved in normal collagen turnover and for the susceptibility to aseptic loosening (Apse et al. 1989;
tumor cell invasiveness. It is expressed in mesenchymal tis- Teronen et al. 1997).
sues during embryogenesis and regenerative remodeling.
The discovery that reduced function of this well-character- Role of SNP in IL‑1 during periprosthetic osteolysis
ized gelatinase/collagenase leads to an inherited osteolytic
and arthritic disorder has provided increased understand- The typical variation in the IL gene cluster may contribute to
ing of the in vivo function of MMP1 (Kanwar et al. 1999). implant failure because IL-1, IL-2, and IL-6 have been pro-
Presumably, MMP-1 is crucial for extracellular matrix and posed to have a role in controlling the genetic risk of implant
bone solubilization. Henceforth, a lack of activity would be failure (Gallo et al. 2009; Lin et al. 2007). Evidence shows
expected to cause an osteopetrotic phenotype, but that is not that wear debris stimulated macrophages secretes IL-1 fam-
the case, indicating that the mechanism by which MMP-1 ily of cytokines. These cytokines are present in high quan-
deficit results in bone resorption in this syndrome is not tity in and around synovial fluid (Kim et al. 1998), osteo-
clear (Zhao et al. 2000). One possibility is that a moder- lytic tissues (Stea et al. 2000), and regional lymph nodes
ately degraded extracellular matrix yields discrepancies in obtained from failed joint arthroplasties, while it is rare in
osteoblast bone deposition. Previous studies are citing the stable implants (Hicks et al. 1996). Studies show that these
relationship between normal osteoblast function and colla- cytokines can mediate bone resorption and induces osteo-
gen cleavage support this hypothesis (Karelina et al. 2000). clastic activity. Both IL-1α and IL-1β can bind IL-1 recep-
It has been recently proposed that extracellular matrix tor type I (IL-1RI) and induce cellular signalling. Recently,
breakdown and exclusion involve a homeostatic relationship correlations of the IL-1β and IL-1 receptor antagonist gene
between the competing processes of osteoblastic synthesis polymorphisms with bone mineral density (BMD) was
and osteoclastic bone resorption. Secretion and activation reported in case of susceptibility to osteoporosis (Chen
of MMP1 are involved in inflammation and neovasculariza- et al. 2003). Several experimental studies have been tried
tion, suggesting a role in the development of deep sepsis to study the association of IL-1 gene polymorphisms with
around total hip replacement and an association between bone loss around prosthetic implants (Campos et al. 2005;
the MMP-1 SNP and total hip arthroplasty (THA) aseptic Lin et al. 2007). SNP in IL1R1 was found correlated with a
failure (Rutter et al. 1998). The SNP present in the promoter reduced risk of osteolysis following THA and with enhanced
region of the gene might directly affect the expression level; IL-1 receptor antagonist mRNA expression (Gordon et al.
however, the process of MMP gene regulation is still not 2008). Another study analyzed the role of SNP in IL1α and
completely defined. It is likely that more functionally impor- IL-1β genes concerning bone loss around dental implants.
tant elements in the promoter region are yet to be identified It was observed that IL-1β-511 genotype is related with the
(Ye 2000). Regarding MMPs exclusively as agents of the early marginal bone loss around dental implants. Effect of
extracellular matrix, obliteration may be too simplistic as IL-1β was seen to be enhanced at early stages of healing and
many of them also displays shielding and anti-inflammatory then reduced at later stages (Lin et al. 2007). A correlation

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of smoking and IL-1 gene polymorphism as risk factors to the effect of the allelic variants on the severity of osteolysis
the susceptibility of peri-implant bone loss after prosthetic in potential future studies in vivo models and account for
reconstruction was also proposed (Feloutzis et al. 2003). the interaction between wear rate and genotype during the
SNP in the promoter region of IL-2 affects the transcrip- pathogenesis of osteolysis.
tional activity of IL-2 and are linked with several diseases.
However, it was observed that the polymorphism in the Other SNPs affecting periprosthetic osteolysis
promoter region of IL-2 does not constitute a genetic risk
factor for dental implant failure (Campos et al. 2005). In Apart from the discussed SNPs in various effector mole-
contrary, Gallo et al. reported that SNP in the IL-2 gene cules, several other molecules, critical during aseptic loosen-
is a critical factor associated with premature THA failure ing of implants, have been implicated as a cause of osteolysis
and severity of acetabular osteolysis. The study proposed around prosthetics. TNFα is one of the other pro-inflamma-
a protective function of IL-2 genetic variant during severe tory cytokines that has been known to play a crucial role
osteolysis (Gallo et al. 2009). Therefore, it appears that func- during aseptic loosening (Lee et al. 2012b). Higher levels of
tional polymorphisms in IL genes are somehow associated TNFα are observed in osteolytic lesions, synovial fluid, and
with susceptibility to implant failure or marginal bone loss the vicinity of implants retrieved from patients with failed
around implants. Nevertheless, more future studies would prosthetics (Ingham et al. 2000). Lately, it has been proposed
be required to delineate the exact role of SNPs in the human that SNP in the promoter region (TNF-238A) of TNFα is
population. related with the increased incidences of aseptic loosening in
comparison to noncarriage. The study suggested that genetic
Role of SNP in IL‑6 during periprosthetic osteolysis and environmental factors can influence the survival rate
of implants after THA (Wilkinson et al. 2003). However,
IL6 (a pleiotropic cytokine) promotes the recruitment and the study also observed that SNP in the promoter region of
maturation of osteoclast precursor cells, is involved in the TNFα (TNF-308A) is not associated with osteolysis. Kolun-
regulation of bone metabolism, the acute-phase response dzic et al. also supported this finding that SNP (TNF-308A)
and the immune response (Koulouvaris et al. 2008). IL6 in TNFα is not related to the onset of aseptic loosening after
induces osteoclast activity and bone resorption by an indi- THA (Kolundzic et al. 2006). Conversely, Gallo et al. dem-
rect process whereby osteoblasts produce downstream effec- onstrated that carriers of SNP (TNF-308A) in the TNFα pro-
tors, such as RANKL (Fig. 2). The transcriptional activity moter region have a risk of premature failure of prosthetics
and plasma levels of IL6 are related with a single G/C base and are susceptible to osteolysis (Gallo et al. 2009). Contra-
exchange SNP within the 5′ flanking region of the gene dictive outcomes for the SNPs in TNFα from separate studies
(Fishman et al. 1998; Hulkkonen et al. 2001)and has been warrants further extensive research approaches to validate
linked with numerous diseases (Malik et al. 2007). Recently, these findings and establish any role of TNFα polymorphism
SNP in the gene promoter region of IL6 (allele IL6-174*G) in susceptibility to osteolysis.
has been implicated in the pathogenesis of aseptic loosen- SNP in signal sequence of TGF-β1 has been analyzed
ing of implants (Gallo et al. 2009). However, another study for its sensitivity to implant failure. It was observed that
found that IL6 (G-174C) SNP is not associated with the early a transition (29T → C) in signal sequence of TGF-β1 is
dental implant failure (Campos et al. 2005). Henceforth, it related to the onset of aseptic loosening of the implants after
is being debated that IL6-174 variant might be responsive THA (Kolundzic et al. 2006). The G-protein Gαs has been
toward the complex local environment around the pros- reported to be involved in pathophysiology of bone. Specifi-
thetic implant area and thus might differentially affect IL6 cally, it has been recognized as a critical regulator of IL-6. It
expression. Another study found an association of IL6 SNP was observed that SNP (GNAS1 T393C) could have a gen-
at position-597 and -572 in the promoter region with early der-dependent role in susceptibility to wear debris induced
prosthetic failure (Kolundzic et al. 2006). osteolysis (Bachmann et al. 2008). Recently, bone formation
Nevertheless, functional studies in this area are required pathways have also been reported to possess SNP variations
to describe the likely role of allelic variant on bone resorp- and contribute to susceptibility of an individual to osteolysis.
tion activity in clinically appropriate in vitro models of wear For example, variations among WNT signalling pathway
debris-induced osteolysis. Additionally, at an epidemiologic antagonists like secreted frizzled-related protein-3 (sFRP3)
level, current advances in medical imaging of osteolytic have been found associated with both heterotopic ossifica-
lesions through computed tomography (CT) and magnetic tion and osteolysis susceptibility (Gordon et al. 2007). WNT
resonance imaging (MRI) might allow accurate volumetric signalling pathway is involved in the regulation of skeletal
assessment of osteolytic lesions about implant wear debris function and stimulate new bone formation (Sharma et al.
to the IL6 proteins encoding gene (Clay et al. 1996; Walde 2013). SNP (FRZB A200T) in sFRP3 was reported to be a
et al. 2005). These techniques may be utilized for evaluating positive marker for susceptibility to periprosthetic osteolysis,

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Genes & Genomics

following THA (Gordon et al. 2007). Other genes, related (Learmonth et al. 2007). However, limitations do still exist.
to WNT signalling pathway, that have been proposed to be These analyses are still costly and need cutting-edge geno-
associated with susceptibility to osteolysis includes, low typing technology and tremendous amounts of raw data to
density lipoprotein receptor-related protein (LRP)5, LRP6 yield appropriate conclusions (Devlin et al. 2001).
and sclerostin. TIRAP is another molecule that have been In this situation, the entire genome sequencing of selected
recently highlighted for its association with susceptibility individuals whose phenotype is extensively characterized
to osteolysis (MacInnes et al. 2015). TIRAP is an adapter and extreme may be inexpensive and offer more valuable
molecule which is involved in bridging MyD88 to receptor results. Another progress in the genetic field is known as
complex of TLR-2 and TLR-4 for modulating many inflam- next-generation sequencing (NGS) technology, which com-
matory pathways (Greenfield et al. 2010). TIRAP rs8177375 prises genome sequencing, transcriptional profiling (RNA-
has been found to be associated with ability to implant fail- Seq) and high-throughput surveys of DNA–protein interac-
ure. At aseptic interface membrane, macrophages express tions (ChIP-Seq). The advantages of NGS may change the
various kinds of pro-apoptotic markers (Landgraeber et al. landscape of genetic analysis by offering high throughput
2008). Moreover, at interface membrane macrophages also results at a reasonable cost (Mardis 2008). Despite rais-
suffers from apoptosis during induction of periprosthetic ing new challenges, in particular in processing, analyzing
osteolysis (Huk et al. 2001). Considering the importance and inferring data, this type of application may explain and
of apoptosis during wear debris-induced osteolysis, SNP increase knowledge about physiologic pathways of bone
in an apoptotic factor like Bcl-2 was also analysed for the remodeling and osteolysis. Moreover, factors such as genetic
risk and time susceptibility to osteolysis after THA. Bcl-2 variation, environment, implant variations, and surgical dif-
is an anti-apoptotic protein which regulates the process of ferences all contribute toward the patient’s risk for osteol-
apoptosis. A SNP in the promoter region of the BCL2 gene ysis. Even then, candidate gene approaches such as those
(− 938C>A) was observed to influence the initiation and discussed earlier require replication in independent cohorts
progress of aseptic loosening (Stelmach et al. 2016). Other to be considered valid (Malchau et al. 2002). The human
than the discussed molecules, SNP in various other fac- genome project has contributed to the advancement of new
tors, know to affect osteolysis, has also been studied but no methods for analysis of the genetic contribution to osteoly-
significant relationship could be established. These factors sis (Shanbhag et al. 2007). The genome-wide analysis will
include, MMP2, MMP4, calcitonin, alpha-calcitonin gene- ultimately permit a complete understanding of the genetic
related peptide (α-CGRP) and vitamin D receptor (Aydin- risk factors related to SNPs and their relevance in osteolysis.
Yuce et al. 2018; Malik et al. 2007). Taking into account the current medical treatments avail-
able for osteolysis, increased efforts in basic science and
clinical research is urgently required to develop novel strat-
Future directions for identifying the role egies for gaining knowledge for effective evaluation and
of genetic variance in periprosthetic proper treatment of patients dealing with implant debris-
osteolysis related osteolysis.

Despite advances, the precise number, identity, and part

of modulatory factors that lead to successful implants and Conclusion
implant maintenance are still mostly unknown, limiting
genetic analysis approaches based on functional candidate A fundamental challenge in hip or knee or dental arthroplas-
genes. The challenge then is to map all the complex genes, a ties is wear generated from prostheses, which is subsequent
considerably tricky task as the total human genome consists in the development of pathological osteolysis. Wear debris
of at least 30,000 genes (Baltimore 2001) and 4.1 million stimulated, activated macrophages elicit responses in a vast
SNPs currently cataloged in public databases. This exceed- number of pathways leading eventually to uncoupling of
ingly high throughput SNP genotyping technology may the osteoblast/osteoclast balance, resulting in osteolysis.
result in the advancement of association-based case–control Individual host response might clarify why comparable
design covering the whole genome (Hirschhorn and Daly bone defects are not witnessed in individuals with similar
2005). Of all the SNPs identified in the research study, SNPs prosthetic wear rate. Preventive measures might be recom-
found in intronic DNA may affect splicing and mRNA syn- mended to the patients at high risk of early osteolysis devel-
thesis; and missense SNPs in exons might affect the function opment (individual susceptibility) in the future. It could be
of the encoded protein product. Clues to the role of SNPs based on documentation of significant functional alleles for
rely only on the nucleotide sequences analysis; additional the cytokines, adhesion molecules, prostanoids, or any other
functional protein product analysis of these SNPs is required proteins involved in osteoclast maturation and activation
to uncover the molecular mechanism related to osteolysis associated with increased osteolysis risk.

13
 Genes & Genomics

However, studies should not be focused only on selected CALCA polymorphisms and aseptic loosening after primary
candidate genes or few identified pathway-related genes. total hip arthroplasty. Biomed Res Int 2018:3687415
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This specific gene or pathway-related gene targeting stud- W, Wedemeyer C (2008) Gender-dependent association of the
ies often suffer from several limitations which include, few GNAS1 T393C polymorphism with early aseptic loosening after
sample sizes resulting in low statistical abilities to detect total hip arthroplasty. J Orthop Res 26:1562–1568
modest to insignificant effect sizes, often associated with Baltimore D (2001) Our genome unveiled. Nature 409:814–816
Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone
most complex diseases, and inadequate coverage of variant modeling and remodeling. Arch Biochem Biophys 473:139–146
across the genes of importance. Inadequate understanding Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation
of the etiopathogenesis of the particular illness also lim- and activation. Nature 423:337–342
its the selection of desired genes and eludes variation in Caicedo MS, Desai R, McAllister K, Reddy A, Jacobs JJ, Hallab NJ
(2009) Soluble and particulate Co-Cr-Mo alloy implant metals
genes involved in previously unpredicted pathways. Contra- activate the inflammasome danger signaling pathway in human
rily, genome-wide related studies exploit a hypothesis-free macrophages: a novel mechanism for implant debris reactivity. J
approach allowing the analysis of a set of extremely inform- Orthop Res 27:847–854
ative markers capturing genetic variants across the whole Campos MIG, dos Santos MCLG, Trevilatto PC, Scarel-Caminaga
RM, Bezerra FJ, Line SRP (2005) Interleukin-2 and interleu-
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of allelic variants (polymorphisms) in the single nucleotides potential inhibitors for osteoporosis: new hope and possibilities.
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cellular response to prosthetic wear particles and to demon- Charnley J (1972) The long-term results of low-friction arthroplasty
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Childs LM, Paschalis EP, Xing L, Dougall WC, Anderson D, Boskey
Acknowledgements  This research was supported by Hallym University AL, Puzas JE, Rosier RN, O’Keefe RJ, Boyce BF et al (2002)
Research Fund and by Basic Science Research Program through the In vivo RANK signaling blockade using the receptor activator of
National Research Foundation of Korea (NRF) funded by the Ministry NF-kappaB: Fc effectively prevents and ameliorates wear debris-
of Education (NRF-2017R1A2B4012944). induced osteolysis via osteoclast depletion without inhibiting
osteogenesis. J Bone Miner Res 17:192–199
Choe W-S, Kim H-L, Han J-K, Choi Y-e, Seo B, Cho H-J, Yang H-K,
Compliance with ethical standards  Park K, Park J-S, Park H (2012) Association between OPG,
RANK and RANKL gene polymorphisms and susceptibil-
Conflict of interest Supriya Jagga, Ashish Ranjan Sharma, Manojit ity to acute coronary syndrome in Korean population. J Genet
Bhattacharya, Chiranjib Chakraborty and Sang-Soo Lee declare that 91:87–89
they have no conflict of interest. Clay FE, Tarlow JK, Cork MJ, Cox A, Nicklin MJ, Duff GW (1996)
Novel interleukin-1 receptor antagonist exon polymorphisms
and their use in allele-specific mRNA assessment. Hum Genet
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