Anterior shoulder dislocations contribute 96–98 % of all shoulder dislocations. The incidence of first-time anterior shoulder dislocation ranges from 8 to 8.2/100,000 population/year [5]. Shoulder instability is often observed after the initial episode of shoulder dislocation, with a recurrence rate of up to 100 % in young athletes. [6] The anterior glenohumeral joint capsule is affected in 90 % of shoulder dislocations after a traumatic shoulder dislocation [7], with patients presenting a plastic deformation of the capsule, which results in capsular laxity [8]. The anteroinferior (AI) region of the capsule is the site most often injured and was described as the real pathogenic pattern of the shoulder dislocation [8, 9]. Whether the AI capsule is previously a more fragile area propense to plastic deformation or it gets damaged after the traumatic episode is currently unknown.

A genetic propensity may give a contribution to it; therefore, genetic research is expanding increasingly within orthopaedics. There is a growing body of evidence that positive directional selection has a pervasive impact on genetic variation within and between species [10, 11]. A great deal of emphasis has therefore been placed on identifying the population genetic signatures of adaptation, in hopes of revealing the genetic basis of recent phenotypic innovations. Typically this is done by investigating genetic variation at a locus of interest using one or more summary statistics capturing information about allele frequencies [12–16], linkage disequilibrium [17, 18] or haplotypic diversity [19, 20] and asking whether the values of these statistics differ from the expectation under neutrality [21].

A “genetic” approach is now being given at shoulder instability, opening the first steps to genetic studies. Clinical association of recurrent dislocation of the shoulder and of the patella with familial joint laxity also suggests an inherited genetic predisposition [22]. Later, gene variants (COL1A1, COL5A1 and COL12A1 genes) previously associated with ACL injury risk were in large part also associated with joint laxity [23].

The healing process in damaged ligament/capsule is complex and requires deposition and accumulation of newly synthesised structural proteins as well as degradation of old or damaged structures composed mainly of the extracellular matrix (ECM) [24].

The capsule is composed of cellular and fibrous elements. Types 1, 3 and 5 fibrillar collagens are the most common types present in the shoulder capsule [25]. Mutations in genes encoding the collagens have been identified in osteogenesis imperfecta [26] and in most forms of Ehlers–Danlos syndrome (EDS) [27] which present frequent joint dislocations, including dislocations of the shoulder. Thus, alterations in these genes may also play a role in shoulder instability.

The anteroinferior (AI) portion of the glenohumeral capsule of shoulder instability patients commonly exhibits macroscopic alteration such as the capsular deformation that is observed during arthroscopic treatment [8]. Previously, a macroscopic analysis of the collagen fibre bundle architecture in the AI region of the glenohumeral capsule revealed that a system of bundles spirally crossing one another permits the entire capsule to resist tensile and shear loads [28]. Later, Wang et al. suggested there is a reciprocal load-sharing relationship in the capsule, whereby tensile load in either the anterior or superior structures is simultaneously accompanied by laxity in the posterior or inferior portion, respectively. So, the complex structure of the joint capsule would suggest that the capsular cylinder has to be regarded as a functional entity, and this biomechanical concept should be considered for the stabilising effect [8].

Corroborating to these findings, Belangero et al. [29] published the first study to detect collagen gene expression alterations in the glenohumeral capsule of shoulder instability patients compared to controls. The COL1A1 and COL3A1 expression were increased not only in AI portion but in all sites, including anterosuperior (AS) and posterior (P) portions of the capsule that may be indicative of a global biomechanic tissue disorders suggesting that anterior shoulder dislocation might lead to molecular alterations across all the capsule even in patients without multidirectional instability. Moreover, COL1A2 was also upregulated in the AS and P sites of the capsule of shoulder instability patients. Upregulation of these genes or their protein products has been reported in several joint injuries, including injured Achilles tendon [30], anterior cruciate ligament [31, 32] and rotator cuff tear [33, 34].

Collagen type 1 (COL1) is the most prominent protein of the capsule, as well as of ligaments and tendons, and the primary protein responsible for resisting physiological loads for different activities. In turn, collagen type 3 (COL3), with its ability to form extensive cross-links, seems to modulate the growth in the diameter of the collagen fibrils [35]. During joint healing, COL3 is postulated to form the architecture of an early repair construct, which is then infiltrated and replaced with COL1. In tendons, it has been suggested that the ratio of COL1/COL3 may be an indicator of total repair response, with the early increase of COL3 initiating the repair, the later increase of COL1 reflecting maturation and the return to baseline ratio level indicating conclusion of the repair process [36].

We detected an imbalance in the expression ratio of several collagen genes, suggesting that the repair process was still incomplete, particularly in the AI site [29]. These molecular alterations may lead to modifications of collagen fibril structure and of the tissue healing process, as well as to capsular deformation. Therefore, the expression of COL1A1, COL1A2, COL3A1 and COL5A1 may play a role in shoulder instability.

Later Belangero et al. [37] evaluated the expression of transforming growth factor b1 (TGFb1), transforming growth factor bR1 (TGFbR1), lysyl oxidase (LOX), PLOD1 and PLOD2 mRNA in these three sites of the glenohumeral capsule in patients with traumatic anterior shoulder instability and controls.

An increase of TGFb1 accompanies the acute inflammatory phase and appears to act as a signal that modulates the production of matrix macromolecules by fibrogenic cells at the injury site [38]. In the shoulder capsule of patients with adhesive capsulitis, TGFb1 was associated with fibrosis and accumulation of a dense matrix of type 1 and type 3 collagen within the capsule [39, 40]. TGFb1 regulates important collagen-modifying enzymes, such as the lysyl oxidase (LOX) that plays a key role in the maturation of the extracellular matrix and is also essential to maintain the tensile and elastic features of connective tissues [41] and lysyl hydroxylases 1 and 2 (encoded by PLOD1 and PLOD2) [42–44]. In many pathological fibrotic situations, the expression of the cross-linked enzyme LOX and its enzymatic activity are controlled by TGFb1. Additionally, differential variations of TGFb1 were able to induce the LOX activity in an in vitro model of mechanical injury in ligament cells [45].

We found increased PLOD2 expression in the macroscopically injured (anteroinferior) region of the glenohumeral capsule of shoulder instability patients [37]. PLOD2 is a lysyl hydroxylase that hydroxylates the telopeptides [46]. Therefore, the shoulder dislocation episode may lead to PLOD2 upregulation in an attempt to heal the capsule through the cross-linking of the new collagen fibrils by the hydroxyallysine route in the injured tissue. Upregulation of TGFb1, TGFbR1 and PLOD2 seemed to be related to patients with more than two episodes of shoulder dislocation and with longer duration of symptoms especially in the posterior region of the capsule [37]. TGFbR1 is a key element in the regulation of wound healing; therefore, the continuation of symptoms may contribute to activation of the TGFb pathway in the posterior region.

LOX upregulation seemed to occur only in an initial phase of the disease, and gene expression was inversely correlated to the duration of symptoms. It was significantly higher in patients with only one dislocation episode compared to controls and compared to patients with recurrent dislocations. [37] It is generally accepted that the total amount of enzymatic cross-linking is controlled by the expression of LOX. Several previous studies have demonstrated that collagen cross-link formation directly affects the strength of bones, tendons and ligaments [47, 48]. With concomitant collagen upregulation, we should expect LOX upregulation across the capsule. Therefore, the authors suggest that the lack of LOX upregulation in later phase suggests that the new collagen fibrils may have reduced resistance to mechanical stress.

On the other hand, capsule modifications may occur due to physical activity involving the superior member which can lead to biomechanical and structural capsule modifications, such as capsular tightness, especially in the posterior region [49]. Belangero et al. [37] found PLOD2 and TGFb1 were reduced in the posterior portion and PLOD1 was reduced in the anterosuperior portion of the capsule of patients who undertook physical activity involving the upper limbs compared to those who did not. Although additional investigations are still necessary, they hypothesise that these capsule modifications due to physical activity may explain the reduced PLOD2, TGFb1 and PLOD1 expression in the capsule of a subgroup of patients [37].

Therefore, genetics may play an important but still unclear role in shoulder instability represented by this moment by the expression of COL1A1, COL1A2 and COL3A1 and also TGFb1, TGFbR1, LOX and PLOD2 [29, 37]. Whether it corresponds to previously inherited characteristics or the consecutive shoulder dislocations are an adaptation to the traumatic process and sports activities is not clearly known.

Further we believe that in the future, knowing the gene expression profile of patients with shoulder instability can help to identify new risk factors, understand more about genetic inheritance and thus help to avoid mistakes of surgical indication, failure to recognise capsular laxity and under-appreciation of technical decisions and missed associated pathology. More high-quality research is required to better understand and characterise this spectrum of conditions so that successful evidence-based information can clarify causal pathways and provide a clue for therapeutic targets.