Variants of FOXO3 and RPA3 genes affecting IGF-1 levels alter the risk of development of primary osteoarthritis

in European Journal of Endocrinology
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  • 1 Division of Endocrinology, Department of Medicine and Center for Endocrine Tumors Leiden
  • | 2 Department of Biomedical Data Science, Section Molecular Epidemiology
  • | 3 Department of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, the Netherlands
  • | 4 Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
  • | 5 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
  • | 6 Department of Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

Correspondence should be addressed to I C M Pelsma; Email: i.c.m.pelsma@lumc.nl
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Introduction

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.

Methods

Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.

Results

Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04–1.17), P=0.002 vs females OR = 1.04 (1.01–1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18–0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20–2.99), P = 0.006).

Conclusion

Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

Abstract

Introduction

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.

Methods

Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.

Results

Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04–1.17), P=0.002 vs females OR = 1.04 (1.01–1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18–0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20–2.99), P = 0.006).

Conclusion

Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

Introduction

Primary osteoarthritis (OA) is a prevalent joint disease, characterized by the degradation of articular cartilage and bone remodeling, of which the exact pathophysiological mechanisms remain unknown (1). To date, OA is considered to be multifactorial, since various risk factors, for example, age, sex, BMI, hormonal and local biomechanical factors, and genetic predisposition play a role (2, 3, 4).

The OA pathophysiological process is linked to enhanced, growth plate-like, metabolic activity of articular chondrocytes, and alterations in the bone formation–resorption process. OA chondrocytes undergo proliferation and hypertrophic differentiation, accompanied by disturbed cartilage homeostasis favoring degenerative changes (5). Furthermore, increased bone turnover, and subsequent vascular invasion from subchondral bone into cartilage, results in the development of osteophytes, which are associated with joint symptoms and decreased quality of life (6). One of the strongest stimulators of chondrocyte proliferation is growth hormone (GH), which affects chondrocytes predominantly via insulin-like growth factor-1 (IGF-1) (7). Systemically, IGF-1 exerts its anabolic actions when unbound to binding proteins, for example, the abundant IGF binding protein-3 (IGFBP-3). IGF-1 has paracrine effects on epiphyseal cartilage, where it stimulates chondrocyte clonal expansion and maturation (8). Moreover, IGF-1 promotes the formation of functional collagen networks through increased proteoglycan and collagen deposition (9).

Mechanistically, IGF-1 is potentially involved in OA pathogenesis. In vitro and in vivo, IGF-1 enhances chondrocyte proliferation, differentiation and survival, and collagen/proteoglycan synthesis (10, 11, 12, 13, 14). Moreover, in acromegaly patients, who suffer from pathologically high GH and IGF-1 levels, GH and IGF-1 levels were related to both OA onset and progression, resulting in a characteristic radiographic OA phenotype of severe osteophytosis with preserved or even widened joint spaces (15, 16, 17, 18, 19, 20). In primary OA, however, the role for IGF-1 in OA pathogenesis is less clear, with only a few studies investigating the association between serum IGF-1 levels and primary OA, reporting inconsistent results (15, 21). Since heritability for serum IGF-1 levels is high (40–60%), genetic variants associated with IGF-1 levels are of interest (22, 23, 24). Associations were observed between primary OA and promotor region polymorphisms of the IGF-1, IGF-1 receptor (25, 26, 27) and the exon 3 deletion of the GH receptor (d3-GHR) gene, increasing GH responsiveness (21). A genome-wide association study (GWAS) uncovered SNPs in the sparc/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2), IGFBP3/tensin-3 (TNS3), replication protein A3 (RPA3) and forkhead box O3 (FOXO3) genes, which robustly influenced serum IGF-1 levels, as candidates for further association studies (28, 29).

Here, we aim to disentangle the role of IGF-1 levels in primary OA pathogenesis, hypothesizing that higher innate IGF-1 levels may increase the risk of primary OA. Hereto, we performed integrated analyses of serum IGF-1 and IGFBP-3 levels and several robust genetic variants, which were previously reported to alter serum IGF-1 and IGFBP-3 levels, in patients with generalized familial primary OA and controls.

Subjects and methods

Ethical statement

The Genetics osteoARthritis and Progression (GARP) Study and Leiden Longevity Study (LLS) were approved by the Medical Ethics Committees of the Leiden University Medical Center (LUMC), and all participants gave written informed consent.

Study design

A case–control design was applied, comparing patients with generalized familial primary OA with controls. Serum IGF-1 levels were measured in cases and controls, whereas IGFBP-3 levels were only measured in controls. To assess the effects of genetic variants on IGF-1 levels and primary OA, 10 SNPs with the largest effect size on circulating IGF-1 levels were selected (28, 29). Outcome parameters were primary generalized OA, with serum IGF-1 and IGFBP-3 levels, and the different SNP genotypes as determinants.

Patient selection: primary OA cases

The GARP Study aimed at identifying determinants of OA susceptibility and progression, consists of 191 sibling pairs (n = 382) of Caucasian Dutch ancestry, and was used to provide cases with generalized familial OA (30). All patients were diagnosed with primary, symptomatic OA at multiple joints in the hand, or in ≥2 joints of hands, spine, knee, or hip, following the combined clinical and radiographic criteria of the American College of Rheumatology (ACR), as described previously in more detail (30, 31, 32, 33, 34). Because of the familial, systemic nature of the disease, this cohort was considered optimal for genetic analyses. Baseline data were used. Details on recruitment and phenotype description are reported elsewhere (30).

Conventional radiographs of the knees, hips and hands were scored according to the Kellgren & Lawrence (KL) scale (35) by a single experienced musculoskeletal radiologist (H.K.); with good corresponding ICCs (30). Radiographic OA was defined using ROA scores, a proportionate score for each joint site based on the number of joints with radiographic OA, as defined by a KL score of ≥2 per joint, according to the following definitions, as described previously (36): ROA scores for knees and hips ranged from 0 to 2 representing no, unilateral, or bilateral radiographic OA, respectively; ROA scores for hands ranged from 0 to 2, with ROA 0 defined as 0–2 affected hand joints, ROA 1 as 3–6 affected hand joints ROA 1 and ROA 2 as ≥7 affected hand joints (based on the number of OA joints, evaluating distal interphalangeal (DIP) joint 2–5, proximal interphalangeal (PIP) joint 2–5, interphalangeal joints 1, and carpometacarpal (CMC) joint 1).

In total, 337 patients were included with subsequent SNP analyses, since serum IGF-1 levels were available in 340 patients, of whom three patients had an incomplete radiographic set.

Controls

The LLS included 421 Dutch Caucasian families: long-lived siblings with their offspring and the partners of this offspring (37). Families were eligible to participate in the study when at least two long-lived siblings were alive and over 89 years old (males) and over 91 years (females), representing less than 0.5% of the Dutch population in 2001. Offspring of these long-lived siblings and their partners were included as controls. There were no selection criteria on health or demographic characteristics. For the present study, 456 individuals with available serum IGF-1 levels were included as controls. At a later stage, SNP analysis was performed for these 456 participating individuals. In control subjects, radiographic OA was not systematically assessed.

Serum IGF-1 and IGFBP-3 measurements

Blood samples were collected at the time of inclusion, and serum aliquots were stored at −80°C. Serum IGF-1 concentrations were measured by an immunometric technique (Immulite 1000, Siemens Medical Solutions Diagnostics, Los Angeles, CA, USA, values in nmol/L), available since February 2006, in both patients and controls. Inter-assay variations of this technique at plasma levels of 60 and 400 ng/mL were, respectively, 6.4 and 3.8%, while 25 ng/mL was the lower limit of detection. Only in controls, IGFBP-3 measurements are available. Serum IGFBP-3 levels were measured using the Immulite 2500 (DPC, Los Angeles, CA, USA), as reported previously, of which the variation was below 8% (38).

SNP genotyping

Whole blood samples were used for the isolation of genomic DNA according to standard procedures. For the genetic analyses, based on previous GWAS analyses (28, 29), the following ten quantitative trait loci (QTLs), with the largest effect sizes on IGF-1 levels, were selected for further analysis in our study: rs2153960, rs4946936 and rs2207731 of the FOXO3 gene on chromosome 6; rs856560, rs700753 and rs957755 in the intergenic region between the IGFBP3 gene and TNS3 gene on chromosome 7; rs11769597 of the RPA3 gene on chromosome 7, and rs1245542, rs1245541 and rs1245578 of the SPOCK2 gene on chromosome 10 (Supplementary Table 1, see section on supplementary materials given at the end of this article). First, linkage disequilibrium (LD) for all SNPs was assessed using LD link (39). As shown in Supplementary Fig. 1, the FOXO3 SNPs were in high linkage (R2 varying between 0.804 and 1), which was also the case for the SPOCK2 SNPs (R2 varying between 0.473 and 1), whereas LD was less prominent in IGFBP3/TNS3 and RPA3 SNPs (R2 varying between 0.188 and 1).

Statistical analysis

Data analysis was performed using SPSS for Windows version 25.0 (SPSS Inc.). Differences between OA patients and controls were calculated by one-way ANOVA and independent samples T-test. Correlation analyses were performed using the Pearson’s correlation. Associations were analyzed using linear or logistic generalized estimating equation (GEE) models, reported as β ± s.e.m., and odds ratios (OR), reported as OR (95% CI), were approximated to correct for familial relationships within the GARP Study (40). All analyses were adjusted for known modifying factors, for example, age, BMI, and sex. Given that ten established genetic polymorphisms were studied, P-values <0.05 were considered significant.

Results

Characteristics of the study population

Clinical characteristics of patients with familial generalized primary OA (GARP study, n = 337) and controls (LLS study, n = 456) were shown in Table 1. Radiographic hip, knee and hand OA were present in 25.0, 39.9, and 80.1% of female cases and in 45.9, 37.7 and 49.2% of male cases, respectively. One female patient had bilateral knee prostheses, and six patients (four females, two males) had unilateral knee prostheses. Fourteen patients had bilateral hip prostheses (10 females, 4 males), whereas 20 patients (15 females, 5 males) had unilateral hip prostheses.

Table 1

Clinical characteristics of the study population. Data are shown as mean ± S.D. or n (%), unless otherwise specified, and were stratified for sex when applicable. Radiographic OA was defined as ROA ≥ 1, based on KL ≥ 2 (35).

Primary OA casesControls
TotalFemaleMaleTotalFemaleMale
n33727660456233223
Age, years59.8 ± 7.459.7 ± 7.561.1 ± 6.859.8 ± 6.858.5 ± 6.761.1 ± 6.8
BMI, kg/m227.1 ± 4.827.1 ± 5.027.1 ± 3.425.6 ± 3.725.4 ± 4.425.9 ± 2.8
ROA
 Hip 97 (28.8) 69 (25.0)28 (45.9)NANANA
 Knee133 (39.5)110 (39.9)23 (37.7)NANANA
 Hand251 (74.5)221 (80.1)30 (49.2)NANANA
IGF-1, nmol/L*18.2 ± 6.317.8 ± 6.319.9 ± 6.317.1 ± 4.917.1 ± 5.217.2 ± 4.6
IGFBP3, mg/L**NANANA 4.40 ± 0.884 .50 ± 0.88 4.29 ± 0.86

*IGF-1 levels were significantly different in cases vs controls (P < 0.0001), both in males (P = 0.001), and females (P < 0.0001), as assessed by independent samples T test. **IGFBP3 levels were significantly higher in males compared to females (P = 0.0094), as assessed using independent samples T test.

IGF-1, Insulin-like Growth Factor-1; IGFBP3, Insulin-like growth factor-binding protein 3; KL, Kellgren & Lawrence score;

Table 2

Association between SNPs and IGFBP-3 levels in healthy controls. Analyses were performed in 456 individuals, 233 healthy female controls and 223 healthy male controls. Data are shown as β ± S.E.M., as derived from linear generalized estimating equation models with IGFBP3 levels as the outcome variable. P-values <0.05 were considered significant.

StrataIGFBP3/TNS3RPA3
rs700753rs11769597
β ± s.e.m.Pβ ± s.e.m.P
Total controls0.22 ± 0.06<0.0001−0.12 ± 0.070.018
Female controls0.37 ± 0.09<0.0001−0.26 ± 0.100.007
Male controls0.10 ± 0.080.2090.00 ± 0.090.988

IGFBP-3, insulin-like growth factor binding protein-3; IGFBP3/TNS3, insulin-like growth factor binding protein-3/tensin-3; RPA3, replication protein A3.

Next, the SNPs affecting IGFBP-3 levels were studied in relationship to the presence of generalized primary OA, followed by the stratification for different joint sites. As shown in Table 3, a modest positive association was observed between RPA3 SNP rs11769597 and the presence of primary OA in the overall group (OR = 1.38 (0.96–1.99), P = 0.081), which appeared to be driven by females with knee OA (OR = 1.90 (1.20–2.99), P = 0.006). Therefore, the RPA3 IGFBP-3 QTL rs11769597 confers risk to knee OA in females. As female carriers of RPA3 IGFBP-3 QTL rs1176957 have innate lower levels of IGFBP-3 (Table 2), such low levels may confer risk to knee OA. By contrast, in females, IGFBP-3 QTL rs700753, associated with higher IGFBP-3 levels, was associated with a lower risk of knee OA risk (OR = 0.67 (0.45–0.99), P = 0.042).

Table 3

Association between SNPs affecting IGFBP-3 levels and primary OA. Data are shown as β ± S.E.M. and OR (95% CI), as derived from logistic generalized estimating equation models with OA as the outcome variable. P-values <0.05 were considered significant.

StrataIGFBP3/TNS3RPA3
rs700753rs11769597
β ± s.e.m.OR (95% CI)Pβ ± s.e.m.OR (95% CI)P
Females
 Total OA−0.19 ± 0.150.83 (0.62–1.11)0.2030.32 ± 0.191.38 (0.96–1.99)0.081
 Hip OA−0.06 ± 0.220.94 (0.61–1.45)0.7820.20 ± 0.271.22 (0.72–2.06)0.468
 Knee OA−0.40 ± 0.200.67 (0.45–0.99)0.0420.64 ± 0.231.90 (1.20–2.99)0.006
 Hand OA−0.12 ± 0.150.89 (0.66–1.19)0.4210.29 ± 0.181.34 (0.93–1.92)0.116
Males
 Total OA0.18 ± 0.231.19 (0.77–1.86)0.4350.00 ± 0.511.00 (0.36–2.74)0.813
 Hip OA0.03 ± 0.311.03 (0.56–1.89)0.927−0.12 ± 0.380.88 (0.42–1.86)0.743
 Knee OA0.11 ± 0.371.11 (0.54–2.28)0.774−0.17 ± 0.450.84 (0.35–2.01)0.698
 Hand OA−0.03 ± 0.280.97 (0.59–1.70)0.9270.21 ± 0.321.23 (0.66–2.31)0.519

For Total OA, analyses were performed in 793 individuals, 456 healthy controls (233 females and 223 males, respectively) and 337 cases (276 females and 61 males, respectively); for Hip OA: Analyses were performed in 553 individuals, 456 healthy controls (233 females and 223 males, respectively) and 97 cases (69 females and 28 males, respectively); for Knee OA, analyses were performed in 589 individuals, 456 healthy controls (233 females and 223 males, respectively) and 133 cases (110 females and 23 males, respectively) and for Hand OA, analyses were performed in 707 individuals, 456 healthy controls (233 females and 223 males, respectively) and 251 cases (221 females and 30 males, respectively).

IGFBP-3, insulin-like growth factor binding protein-3; IGFBP3/TNS3, insulin-like growth factor binding protein-3/tensin-3; OA, osteoarthritis; OR, Odds ratio; RPA3, replication protein A3.

IGF-1

Serum IGF-1 levels and the respective QTL SNPs were measured in controls and OA patients, allowing analyses of IGF-1 levels as function of clinical parameters including OA and as function of IGF-1 QTL SNPs (Supplementary Table 1). Supplementary Figure 2 shows that serum IGF-1 levels negatively correlated with age (r = −0.166, P < 0.0001), and BMI (r = −0.098, P = 0.018) in the entire study cohort. When assessing patients and controls separately, the association between IGF-1 levels and BMI appeared lower in the controls (r = −0.071, P = 0.132; Supplementary Fig. 2B). Moreover, as depicted in Table 4, upon stratification for sex, IGF-1 levels were significantly associated with primary OA compared to controls in both sexes, although males demonstrated greater effects (OR = 1.10 (1.04–1.17), P = 0.002) compared to females (OR = 1.04 (1.01–1.07), P = 0.02). Upon additional stratification for joint site, higher IGF-1 levels were found, with similar effect sizes, across different joint sites both in males and females (Table 4). Strongest association was observed in males with hip OA (OR = 1.10 (1.01–1.21), P = 0.031).

Table 4

Associations between IGF-1 levels and the presence of radiographic OA. Data are shown as β ± S.E.M. and OR (95% CI), as derived from logistic generalized estimating equation models with OA as the outcome variable. P-values <0.05 were considered significant.

Strataβ ± s.e.m.OR (95% CI)P
Total
 Total OA0.05 ± 0.011.06 (1.03–1.09)<0.0001
 Hip OA0.06 ± 0.021.07 (1.02–1.12)0.004
 Knee OA0.06 ± 0.021.06 (1.02–1.10)0.005
 Hand OA0.05 ± 0.021.05 (1.02–1.09)0.002
Females
 Total OA0.04 ± 0.021.04 (1.01–1.07)0.02
 Hip OA0.05 ± 0.031.05 (1.00–1.11)0.052
 Knee OA0.05 ± 0.021.06 (1.01–1.10)0.016
 Hand OA0.04 ± 0.021.05 (1.01–1.08)0.013
Males
 Total OA0.10 ± 0.031.10 (1.04–1.17)0.002
 Hip OA0.10 ± 0.051.10 (1.01–1.21)0.031
 Knee OA0.06 ± 0.041.06 (0.97–1.16)0.19
 Hand OA0.07 ± 0.041.08 (1.00–1.16)0.061

For Total OA, analyses were performed in 793 individuals, 456 healthy controls (233 females and 223 males, respectively) and 337 cases (276 females and 61 males, respectively); for Hip OA, analyses were performed in 553 individuals, 456 healthy controls (233 females and 223 males, respectively) and 97 cases (69 females and 28 males, respectively); for Knee OA, analyses were performed in 589 individuals, 456 healthy controls (233 females and 223 males, respectively) and 133 cases (110 females and 23 males, respectively) and for Hand OA, analyses were performed in 707 individuals, 456 healthy controls (233 females and 223 males, respectively) and 251 cases (221 females and 30 males, respectively).

IGF-1, Insulin-like Growth Factor-1; OA, osteoarthritis; OR, Odds ratio.

Next, we explored whether the previously identified IGF-1 QTLs associations were present in our study cohort (28, 29). As shown in Supplementary Table 2, the following FOXO3 SNPs were associated with circulating IGF-1 levels in female patients: rs2153960 (β = −1.02 ± 0.39, P = 0.009), rs4946936 (β = −1.08 ± 0.40, P = 0.006), and rs2207731 (β = −0.87 ± 0.39, P = 0.027). Given that these SNPs were subject to high LD (Supplementary Fig. 1), we used the FOXO3 SNP rs4946936 as proxy of the IGF-1 QTLs. As shown in Table 5, in females FOXO3 SNP rs4946936 was significantly and inversely associated with serum IGF-1 levels (β = −1.08 ± 0.40, P = 0.006), which appeared most pronounced in female primary OA patients (β = −1.28 ± 0.54, P = 0.019). Similarly in males, a strong inverse association between IGF-1 levels and rs4946936 was observed, particularly in primary OA patients, albeit not statistically significant (β = −1.70 ± 1.29, P = 0.189).

Table 5

Association between SNPs and IGF-1 levels.

StrataFOXO3 rs4946936
β ± s.e.m.P
Females
 Total−1.08 ± 0.400.006
 Controls−0.82 ± 0.570.148
 Cases−1.28 ± 0.540.019
Males
 Total−0.29 ± 0.550.602
 Controls0.24 ± 0.580.682
 Cases−1.70 ± 1.290.189

Analyses were performed in 793 individuals, 456 healthy controls (233 females and 223 males, respectively) and 337 cases (276 females and 61 males, respectively). Data are shown as β ± s.e.m., as derived from linear generalized estimating equation models with IGF-1 levels as the outcome variable. P-values <0.05 were considered significant.

FOXO3, forkhead box O3; IGF-1, Insulin-like Growth Factor-1.

Given that the association of rs4946936 with IGF-1 levels was pronounced among both female and male OA patients, we next studied generalized primary OA at different joint sites in relation to IGF-1 levels and the FOXO3 SNP rs4946936. As shown in Table 6, in females, the positive association of IGF-1 levels across different OA strata remained, and was not independently affected by rs4946936 genotypes. In males, both the minor allele of rs4946936 of the FOXO3 gene, as well as IGF-1 levels, showed an independent association with hip OA with OR = 0.41 (0.18–0.90), P = 0.026 and OR = 1.10 (1.01–1.21), P = 0.038, respectively. These findings indicate that, although male hip OA patients have significantly increased IGF-1 levels, the minor allele of the FOXO3 SNP rs4946936 confers significant protection to hip OA.

Table 6

Associations between the presence of radiographic OA, IGF-1 levels and FOXO3 SNP affecting IGF-1 levels. Data are shown as β ± S.E.M. and OR (95% CI), as derived from logistic generalized estimating equation models with OA as the outcome variable. P-values <0.05 were considered significant.

StrataIGF-1rs4946936
β ± s.e.m.OR (95% CI)Pβ ± s.e.m.OR (95% CI)P
Females
 Total OA0.04 ± 0.021.04 (1.00–1.07)0.026−0.10 ± 0.150.90 (0.68–1.20)0.477
 Hip OA0.05 ± 0.031.05 (1.00–1.11)0.055−0.13 ± 0.240.88 (0.55–1.40)0.579
 Knee OA0.05 ± 0.021.05 (1.01–1.10)0.018−0.10 ± 0.200.91 (0.62–1.33)0.910
 Hand OA0.04 ± 0.021.04 (1.01–1.08)0.017−0.12 ± 0.160.88 (0.65–1.19)0.410
Males
 Total OA0.09 ± 0.031.10 (1.03–1.17)0.002−0.17 ± 0.280.84 (0.49–1.45)0.539
 Hip OA0.10 ± 0.051.10 (1.01–1.21)0.038−0.90 ± 0.410.41 (0.18–0.90)0.026
 Knee OA0.05 ± 0.051.05 (0.96–1.16)0.296−0.63 ± 0.500.53 (0.20–1.42)0.531
 Hand OA0.07 ± 0.041.08 (1.00–1.16)0.0630.08 ± 0.341.08 (0.56–2.11)0.814

For Total OA, analyses were performed in 793 individuals, 456 healthy controls (233 females and 223 males, respectively) and 337 cases (276 females and 61 males, respectively); for Hip OA, analyses were performed in 553 individuals, 456 healthy controls (233 females and 223 males, respectively) and 97 cases (69 females and 28 males, respectively); for Knee OA, analyses were performed in 589 individuals, 456 healthy controls (233 females and 223 males, respectively) and 133 cases (110 females and 23 males, respectively) and for Hand OA, analyses were performed in 707 individuals, 456 healthy controls (233 females and 223 males, respectively) and 251 cases (221 females and 30 males, respectively).

FOXO3, forkhead box O3; IGF-1, insulin-like growth factor 1; OA, osteoarthritis; OR, Odds ratio.

Discussion

This is the first study combining assessments of serum IGF-1 levels, genetic variants altering circulating IGF-1 levels and primary OA. Serum IGF-1 levels were higher in patients with primary OA compared to controls, with male OA patients exhibiting a more pronounced effect than females. Independent of this effect of IGF-1 levels on OA, the IGF-1 QTL SNP rs4946936 conferred a significant lower risk to hip OA in males. In females, the rs4946936 effect was absent. Considering IGFBP-3 levels and the IGFBP-3 QTLs rs11769597 and rs700753, female carriers had lower or higher innate IGFBP-3 levels, which may increase or decrease the risk of knee OA.

Serum IGF-1 levels were significantly higher in primary OA patients than in controls at all joint sites, following adjustment for age and BMI, with the highest effect sizes in males. Previously, several studies investigating the role of the GH/IGF-1 axis in primary OA showed inconsistent results, due to heterogenous populations with different sizes, differing OA definitions, and, importantly, no adjustments for age and BMI (21). Therefore, determining whether the increased serum IGF-1 levels are the cause or consequence of primary OA was difficult.

FOXO3 gene QTL, rs4946936, one of ten variants previously associated with serum IGF-1 levels assessed in this study (28, 29), was associated with decreased serum IGF-1 levels in both males and females. Moreover, rs4946936 was independently associated with a decreased risk of primary hip OA in males. In females, however, the aforementioned effect of rs4946936 was absent. Conclusively, male carriers of QTL rs4946936 had lower IGF-1 levels, potentially thereby decreasing the risk of hip OA, whereas current circulating IGF-1 levels were increased when hip OA was present. Although causality is difficult to determine in this cross-sectional study, increased IGF-1 levels appeared to result in the development of primary OA, and the OA process appeared to increase IGF-1 levels. Moreover, conclusions must be drawn with appreciation of the small study population, underlining the need for longitudinal replication studies.

Furthermore, in females, a SNP in the RPA3 gene, rs11769597, was associated with lower circulating IGFBP-3 levels, and increased risk of primary knee OA. Additionally, IGFBP-3 QTL rs700753 exhibited exactly opposite effects. Unfortunately, since IGFBP-3 levels were unavailable in patients with primary OA, the dependency or independency of the aforementioned effects cannot be determined. Nevertheless, males and females appear subject to both similar and different mechanisms surrounding circulating IGF-1 or IGFBP-3 levels and risk of primary OA.

IGF-1 is involved in multiple aspects of bone physiology, including endochondral ossification, skeletal growth, and bone remodeling, since IGF-1 is an important growth-promoting peptide (41, 42). The predominant action of IGF-1 is promoting cellular proliferation, and tissue-specific cell functions, whilst inhibiting apoptosis (43, 44, 45, 46, 47, 48, 49). FOXO3, a transcription factor, induces cell growth arrest and apoptosis (29). When growth factors are absent, FOXOs are present in the nucleus, where they inhibit the cell cycle, promote apoptosis and decrease oxidative stress (50). When growth factors, for example, IGF-1, are present, FOXO phosphorylation occurs, thereby preventing cell cycle arrest and apoptosis (51). Normal, or over-expression of FOXO3A resulted in decreased oxidative stress, and the blockage of pro-catabolic responses, whereas decreased expression of FOXO3 was observed in OA chondrocytes (52). Therefore, FOXOs appear to play a role in cartilage homeostasis and might protect cartilage from OA development. The RPA complex, comprised of replication protein A3 (RPA3) in combination with RPA1 and RPA2, is the predominant single-strand DNA-binding complex in DNA metabolism, and is essential for recombination, replication and repair of DNA (53). To date, no literature on the interplay between GH/IGF-1 and the RPA complex, effects of rs11769597, and the effects of RPA3 in chondrocytes, osteocytes, osteoblasts and osteoclasts, is available.

Serum IGF-1 concentrations, reflecting the circadian oscillating GH concentrations, have been shown to decrease progressively with age in adulthood, and are influenced by for example, estrogens and BMI (54, 55). Moreover, IGFs bioavailability is regulated by IGF-binding proteins. IGFBP-3, the most abundant IGF-binding protein, functions as: transporter of IGFs in plasma, regulator of the direction, efflux and clearance of IGFs, and modulator of IGF–IGF receptor interactions (56). IGFBP-3 decreases the amount of biologically available IGFs, thereby counteracting the effects of IGFs.

As the role of GH and IGF-1 in bone is unequivocal, the GH/IGF-1 axis is regarded a potential candidate for genetic susceptibility studies for primary OA. Several genetic variants in the IGF-1 receptor gene and promotor region of the IGF-1 gene have previously been linked to OA (25, 26, 27). Additionally, the d3-GHR polymorphism, resulting in increased GH-responsiveness, has been associated with an increased risk of predominantly hip OA in females (21). Moreover, one SNP in the IGFBP3 region, rs788748, has been associated with hip OA in a large cohort of primary OA patients (57). Previous research has discovered that IGFBP-3 was abundant inside osteoarthritic cartilage, with more IGFBP-3 worsening the OA characteristics (58, 59, 60, 61, 62), possibly due to the triggering of chondrocyte apoptosis (62). Therefore, increased serum IGFBP-3 levels are hypothesized to counteract the effects of serum IGF-1 concentrations by lowering the biologically active IGF-1, preventing the detrimental effects of free IGF-1 on bone. However, since serum IGFBP-3 levels were not available in our patients, this hypothesis could not be confirmed.

Although the mechanisms remain unclear, males and females are subject to different effects of IGF-1 and IGFBP-3 on primary OA. IGFBPs might play a role in these sex-dependent effects of IGF-1 on bone (63). IGFBP-2-/- and IGFBP-4-/- mice have a sex-dependent altered bone microenvironment (64, 65, 66, 67, 68), with male bone quality being more severely affected. Additionally, inducing early OA resulted in different IGF-1, but similar IGBFP3 expression patterns in male and female rats, with further degeneration in females (69). Currently, these studies have not been performed using human tissue.

Whether circulating IGF-1 and IGFBP-3 levels accurately reflect peripheral activity requires further investigation. Measuring unbound IGF-1 levels, or IGF-1 bioactivity has been reported to reflect the GH/IGF-1 status more precisely, although total serum IGF-1 levels are often used because of methodological difficulties in measuring bioactivity (70, 71). Since IGF-1 acts locally, IGF-1 concentrations in synovial fluid might be more important, though the correlation between serum and synovial IGF-1 levels is unknown. Previously, synovial fluid has been assessed in primary OA patients with varying results. Higher synovial GH levels compared to serum GH levels were observed, whereas synovial IGF-1 levels were decreased (72). By contrast, a doubling of IGF-1 levels in osteoarthritic synovial fluid compared to normal fluid was reported (73). Moreover, increased IGF-1 and IGFBP-3 levels in synovial fluid were found in female, but not in male, knee OA patients (74). Therefore, we hypothesize that there is an optimal concentration of IGF-1 and IGFBP-3 in synovial fluid, which needs to increase to promote healing following damage in a regulated manner, since excessive IGF-1 levels result in OA-like joint alterations.

Several potential limitations need to be addressed. Since the study design resembled Mendelian randomization studies, the sample size (especially males) was relatively small, which might have resulted in insufficient power to detect associations. Moreover, the percentage of females in patients and controls differed (82% vs 51%, respectively). Almost all included women were postmenopausal at the time of assessment, and IGF-1 levels were lower in postmenopausal, compared to equal-aged premenopausal, women (75, 76, 77), which potentially influenced our results. Another limitation is the heterogeneity of the controls, being a combination of offspring from long-lived siblings, who might be healthier than the average population, and the offspring’s partners, a random sample of the general population, both with an unknown radiographic OA status. Therefore, the observed effects of serum IGF-1 levels on OA might be an underestimation of the actual effect. Finally, we measured circulating IGF-1 levels, which might not reflect local IGF-1 concentrations in cartilage, bone and synovial fluid.

In summary, higher serum IGF-1 levels were associated with increased risk of severe familial primary OA at multiple joint sites, especially in males. In addition, several SNPs influencing circulating IGF-1 levels were shown to alter the primary OA risk for specific joint sites. Therefore, the GH/IGF-1 axis is involved in the osteoarthritic process, although the underlying pathophysiological mechanisms remain to be elucidated in future longitudinal studies.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-20-0904.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The LLS was supported by the Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917-66-344 and 911-03-012), Leiden University Medical Center, and by the “Centre of Medical System Biology” and the “Netherlands Consortium of Healthy Aging” in the framework of the Netherlands Genomics Initiative (NGI). Financial support for the GARP study was obtained from the Dutch Arthritis Association (06-1-304) and Pfizer Groton Inc. Furthermore, the research leading to these results has received funding from the Medical Delta, Dutch Arthritis Society, and Dutch Scientific Research council NWO /ZonMW VICI scheme (91816631/528).

Author contribution statement

M Kloppenburg, N R Biermasz and I M Muelenbelt contributed equally to this work.

Acknowledgements

We thank all study participants of the LLS and GARP study. The Leiden University Medical Center has been and is supporting the LLS and GARP study. We are indebted to Drs. N Riyazi, J Bijsterbosch, HM Kroon and I Watt for collection of data in the GARP study.

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    Olney RC, Tsuchiya K, Wilson DM, Mohtai M, Maloney WJ, Schurman DJ & Smith RL Chondrocytes from osteoarthritic cartilage have increased expression of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and -5, but not IGF-II or IGFBP-4. Journal of Clinical Endocrinology and Metabolism 1996 81 10961 1 03. (https://doi.org/10.1210/jcem.81.3.8772582)

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    Mazziotti G, Lania AGA & Canalis E MANAGEMENT OF ENDOCRINE DISEASE: Bone disorders associated with acromegaly: mechanisms and treatment. European Journal of Endocrinology 2019 181 R45R56. (https://doi.org/10.1530/EJE-19-0184)

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    Zhang M, Faugere MC, Malluche H, Rosen CJ, Chernausek SD & Clemens TL Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation. Journal of Bone and Mineral Research 2003 18 8368 43. (https://doi.org/10.1359/jbmr.2003.18.5.836)

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