The association of growth differentiation factor 5 rs143383 gene polymorphism with osteoarthritis: a systematic review and meta-analysis

Osteoarthritis (OA), also considered as chronic arthritis, refers to a degenerative process in the articular cartilage of the joints, subchondral bone reactive hyperplasia, inflammation and osteophyte formation based on joint degeneration or aging, and characterized by joint swelling, pain or dysfunction [1]. OA is a chronic bone and joint disease caused by cartilage degeneration and bone hyperplasia of the joint, also known as proliferative arthritis, degenerative arthritis and osteoarthritis. This disease mostly occurs in the elderly, but also in young people [2]. OA is a major disease that causes joint pain and limited activity in the elderly, and Middle-aged and elderly people suffer from serious health problems as a result of it. Several studies have found that age, joint trauma, obesity and genetic susceptibility are risk factors for OA [3, 4]. Growth differentiation factor 5 (GDF5) is also known as CDMP-1 and BMP-14. It is the growth differentiation factor that regulates tissue growth, and it is bone morphogenetic protein and a member of the transforming growth factor β family, which plays a crucial role in the progression, protection and rehabilitate of bone and cartilage [5]. It has been reported that GDF5 gene mutations can directly lead to some bone-related diseases. The content of GDF5 increases in gradient in the area where cartilage precursor cells gather, the cartilage core where long bones develop, and the joint formation areas, thereby exerting its special biological functions, such as regulating limb bud cell development and maintaining cell dynamic balance [6]. Furthermore, GDF5 also regulates the proliferation and differentiation of limb bud cells in the embryonic stage. In view of GDF5’s vital function, OA is considered to be related to it [7‐9]. Some previous studies considered the correlation between GDF5 and OA, but some studies still believe that there is no significant correlation.

A number of shortcomings have been found in previous meta-analyses, including incorrect data extraction and insufficient analysis of population subgroups. Additionally, some literature has been updated. The main purpose of this article is to make a comprehensive analysis of the association between GDF5 rs143383 SNP and OA in different types of osteoarthritis, such as knee osteoarthritis, hip osteoarthritis and hand osteoarthritis. At the same time, from the analysis of gender and different nationalities, we can get the most accurate conclusion at present, which can be used to guide clinical work and carry out related drug research.

The latest epidemiological study found that 8.1% of people over 45 years old had symptoms of OA, and the highest incidence rate was between 60 and 69 years old. And with the aging of the population becoming more and more serious, it is estimated that over 50-year-olds will account for 49% of the total population by 2050. If we do not conduct in-depth research in this direction, the proportion of elderly people suffering from OA will inevitably increase significantly [28]. Up to now, there is no effective drug to prevent or improve the progress of osteoarthritis in the whole world, and it is still focused on reducing pain and improving joint function [29, 30]. Severe OA seriously affects patients’ actions and pain, resulting in an extremely low happiness index. At present, operation is the main treatment method to eliminate pain and recover joint range of motion [31, 32]. At this stage, the cost of joint replacement surgery is relatively high. With the increasingly serious aging of the population, the social and economic burden of OA treatment will inevitably increase in the future. Therefore, the study on the pathogenesis of OA is urgent and has positive practical significance.

GDF5 participates in tissue differentiation and is related to the various bone-related diseases, which have been confirmed at the genetic level and through molecular biological mechanisms. It can provide help for early diagnosis of bone-related diseases and potential targets for treatment, and further understanding the mechanism of disease development, which can bring many new ideas to medical researchers [6, 33]. GDF5 regulates chondrogenesis through the canonical Wnt signaling pathway. Developmental dysplasia of the hip (DDH) is a multifactorial disease, which occurs under environmental and genetic influence. The genes displaying the most statistically significant co-expression link to GDF5. A specific polymorphism in GDF5 has been linked to DDH, and DDH patients more frequently carry the T allele [6, 34, 35]. This may be closely related to the occurrence and development of OA, possibly through the same mechanism. Studies in UK and Netherland have confirmed that the SNP of GDF5 rs143383 is closely correlated with the incidence rate of OA [11, 15, 16]. However, no correlation was found between OA and GDF5 gene polymorphisms in South Korea and Japanese populations [17, 18], which may be related to the genetic differences between eastern and western ancestors. This conclusion still lacks the correct guiding conclusion and has become the focus of the debate.

The previous meta-analysis data have not been updated [36], and some analyses have recorded identical data [37], which does not fully explain the relationship between GDF5 and OA. The Meta has carried out the most comprehensive analysis at present, analyzing different types of arthritis, gender and race. Although individual data are highly heterogeneous, which affects accurate conclusions, we have analyzed data with low heterogeneity and can still make effective summary because of the combination of numbers, so as to draw relatively more accurate conclusions.

The low heterogeneity gene model was selected for analysis throughout this meta. Based on the results, there was a significant correlation between GDF5 and OA in the total OA codominant heterozygote gene model in all populations with OA of the knee, hip, and hand, Asian populations and Caucasian populations, especially in Caucasian populations codominant homozygote gene model and dominant gene model.

As osteoarthritis differs in type, the correlation of knee osteoarthritis is the most obvious. The association between KOA and GDF5 can be evaluated based on an overall analysis of the four genotypes. In the overall allele gene, codominant homozygote gene, codominant heterozygote gene and dominant gene model, it is shown that there is a relationship between GDF5 gene and KOA. And it suggests the same results in both among Asians and Caucasians. In hip OA, it is generally explained that there is no significant relevance between GDF5 SNP and hip OA, and because of the high heterogeneity, this conclusion needs to be further verified, and the current study of hip OA is mainly Caucasian population and needs more data research and other ethnic groups. In hand OA, the overall analysis of the correlation between GDF5 and hand OA can be evaluated using these two genotypes. Codominant homozygote gene and dominant gene model suggest that GDF5 gene is associated with hand OA. However, the current study is focused on the Caucasian population, and the outcomes should be proved by an abundant case in other ethnic groups.

OA can arise naturally, with the aging population witnessing an increase in diagnoses of this pathology, but the root causes of OA have yet to be identified, and increasing interest is arising toward investigating biological sex as a risk factor. Clinical studies show increased prevalence and worse clinical outcomes for female patients [38, 39]. In the analysis of OA in different genders, we found that GDF5 was associated with OA in both males and females’ osteoarthritis. In males with OA, it is possible to reckon the association between GDF5 gene and OA using four genotypes. In the overall allele gene, codominant homozygote gene, codominant heterozygote gene and dominant gene model, the GDF5 gene is associated with OA, and the same results are suggested in the Caucasian population. In females with OA, three genotypes can be used to evaluate the relevance between GDF5 gene and OA. The overall allele gene, codominant homozygote gene and dominant gene model suggest that GDF5 gene is associated with OA, and the same results are suggested in Asian and Caucasian populations.

At present, it is generally believed that the pathogenesis of OA is due to the imbalance of cartilage tissue synthesis and catabolism, and the destruction of articular cartilage is difficult to repair, and the imbalance of chondrocytes synthesis and catabolism [40, 41]. Many factors are interrelated with the occurrence and progression of OA, such as joint composition and environmental factors, genetic predispositions, endocrine and metabolic diseases and mechanical injuries. Genetic factor is a significant pathogenic risk factor, and the genetic polymorphisms of multiple gene loci have been proved to be interrelated with the occurrence of OA in the region [42‐45]. GDF5 belongs to the family of bone morphogenetic proteins (BMP), which is involved in bone growth and repair, such as the proliferation, differentiation, angiogenesis, and bone and cartilage formation. Research shows that GDF5 genetic polymorphisms are closely related to OA [46, 47]. However, it is not completely clear what role GDF5 plays in the occurrence and development of OA, and how it affects other signal pathways. The transmembrane serine/threonine kinases I and II can initiate GDF5’s signal cascade just like other BMPs. As a result of GDF5 binding, receptors are phosphorylated, the downstream Smad pathway is activated, and Smad is transferred to the nucleus to regulate gene transcription [48, 49]. Additionally, type I receptors bind both GDF5 and BMP2, and their complexes can recruit type II receptors, activating MAPK in the process [50]. Kan et al. [51] found that Sox11 (SRY-related HMG box11) transcription factor regulates the expression of GDF5, and Sox11 overexpressed in vitro and microsphere cell culture can directly activate the increase in GDF5 gene expression in chicken limb bud cells. The binding site of the Sox family is in the 5 ′—UTR region of GDF5 gene, indicating that Sox11 can specifically bind to this site, and the Sox11 can be used as a potential regulatory site of GDF5. However, the specific mechanism remains to be further studied and verified.

The main advantages of this study include: (1) Most of the studies contained in the meta-analysis are high quality case–control studies; (2) based on relatively large samples, we extract and analyze specific gene results. However, the current meta-analysis also has many limitations: (1) Although the meta-analysis contains a relatively large sample volume, it could still lead to overestimation and does not explain all the results; (2) the subjects of the study only include East Asian and Caucasian races and cannot reflect the overall situation. In subgroup analysis, the sample volume of every subgroup is smaller, which will also cause the analysis results to deviate from the actual situation; (3) publication bias and language bias caused by the unpublished results of some negative studies would affect the results of meta-analysis; (4) when patients’ informed consent is required in clinical research, and it comes to medical ethical issues, it is likely to result in low literature quality evaluations and inevitable biases, which will affect the reliability of meta-analysis conclusions; and (5) this paper only includes OA of knee joint, hip joint and hand joint, which is not all OA, and further data are needed to improve it. Therefore, the conclusion demands to be further confirmed by larger sample randomized controlled trials.

Collectively, we concluded that the GDF5 rs143383 SNP has a significant relationship with the occurrence of OA in the whole population with OA of the knee, hip, and hand. From the analysis of each group, we got the same conclusion in KOA and hand OA, but which need further verification in hip OA. Considering gender, we found a close relationship between GDF5 rs143383 SNP and OA of the knee, hip and hand, both for men and women. This conclusion is more obvious in Caucasian people.