So far, four studies have examined PTOA in mice from genetic standpoint. These mouse studies are described below and summarized in Table 13.2.

First, Ward et al. [33] in the laboratory of Steve Olson investigated the correlation between intra-articular fracture healing and OA in C57BL/6 and MRL/MpJ mice. These authors experimentally created intra-articular fractures in the knees of these mice and analyzed the bone and cartilage changes by various techniques. It was found that the MRL/MpJ mouse is protected from PTOA after intra-articular fracture compared to C57BL/6. Second, Lewis and colleagues [34] again from the above research group have shown genetic and cellular evidence of decreased inflammation associated with reduced incidence of post-traumatic arthritis in MRL/MpJ mice compared to C57BL/6 mice undergoing tibial plateau fractures. These data further suggest a genetic association between joint tissue inflammations and the development and progression of PTOA in mice. Third, in the laboratory of Francesco Dell’Accio, Eltawil et al. [29] reported that C57BL/6 mice after experimental cartilage injury developed features of OA compared to DBA/1, which displayed no signs of OA. Fourth and lastly, Hashimoto et al. [35] in our laboratory used two distinct mouse strains (with the ability to heal or not to heal full-thickness cartilage lesions) to induce PTOA through destabilization of medial meniscus [36]. Changes in articular cartilage and bone showed that a mouse strain with healing ability (LGXSM-6) was protected from developing PTOA compared to the other mouse strain, which failed to heal its injured articular cartilage (LGXSM-33) and developed PTOA (Fig. 13.2). As stated above, these mouse strains are recombinant inbred strains of mice and have distinct genetic portfolio, therefore providing a direct evidence for the genetic variation in the development of PTOA in mice.

Since the start of the twenty-first century, several efforts have been focused on the search for QTLs that predispose to OA. Small- and large-scale GWAS, genome-wide linkage analysis, gene-based association studies, and candidate gene studies reflect the current status quo of the genetics of complex diseases such as OA. Several GWAS studies have been conducted to understand the involvement of genetic basis of deadly human diseases. Figure 13.3 shows the number of GWAS studies for common (complex) diseases. Note that numbers of GWAS studies for OA are more than other deadly diseases such as HIV, cardiovascular problems, and obesity and lag behind Alzheimer’s disease, diabetes, and cancer.

The candidate gene association studies have been very successful since they are directed toward identifying susceptible loci for OA. While the scope of candidate gene association studies is broad, it would be injustice not to mention those studies, which have identified some of the important genes such as aspirin gene ASPN [37], SMAD3 gene [38], GDF5 gene [38–40], and FRZB gene (Table 13.3). These genes passed the strict criteria of replication in diverse Asian and European populations as well as the demonstration of functional significance. However, these findings are still debatable because of several shortcomings in the candidate gene association studies, such as lower sample size, the sparse coverage of markers employed by the relatively low-density microsatellite maps of linkage scans, and too many reports being false positive (mainly because of stringency of observed p values). These shortcomings have largely been removed by the GWAS recently (listed in Table 13.3). These GWAS studies fulfilled these criteria: genetic variants for which data was available from at least one replication cohort and P value adjusted for multiple comparisons.