Collagens represent the predominant protein class in mammals, accounting for approximately 30% of the total protein mass and serving as a fundamental component of the extracellular matrix (ECM). This protein family encompasses 28 distinct subtypes, ranging from type I to type XXVIII, with type I collagen being the most prevalent, constituting about 90% of the body’s collagen [17]. Each collagen subtype is capable of forming either a homotrimer or a heterotrimer, which are composed of three alpha chains.

The biosynthesis of these alpha chains initiates with the formation of procollagen, characterized by the presence of N-terminal and C-terminal propeptides. This procollagen undergoes a conformational change to form a triple helix structure within the cytoplasm. Following secretion from the cell, a critical post-translational modification occurs wherein both the N- and C-terminal propeptides are excised by specific proteinases. This process facilitates the subsequent crosslinking and assembly of the collagen molecules into fibrils, which is pivotal for their functional integration into the ECM [18,19]. This intricate process of collagen synthesis and assembly is crucial for maintaining the structural integrity and functional properties of the ECM in various tissues.

Collagen, a principal constituent of the extracellular matrix (ECM), is indispensable for the normal functioning of tissues, playing a pivotal role in sustaining the stability and structural integrity of both tissues and organs. Among its various forms, collagen type I alpha 1 chain (COL1A1), a key element of type I collagen, is extensively distributed across the body, particularly within the interstitial spaces of parenchymal organs and connective tissues. This wide distribution underscores its significance in facilitating tissue development and maintaining homeostasis [20].

Ligaments and tendons, key structural components in the human body, are composed of collagenous bands of fibrils, which include a variety of collagen types, proteoglycans, and glycoproteins [21]. Among these, Type I collagen is the predominant protein, accounting for 70–80% of the dry weight of ligaments [22]. This specific collagen molecule is a heterotrimer, composed of two alpha-1 (I) chains and one alpha-2 (I) chain, with the genes COL1A1 and COL1A2 responsible for encoding these chains, respectively [23].

The COL1A1 gene, in particular, has garnered significant attention due to its association with various medical conditions. Notably, the Sp1 binding site polymorphism within COL1A1 has been linked to an increased risk of cruciate ligament ruptures [24]. Additionally, mutations in the COL1A1 gene have been identified as causal factors in monogenic connective tissue disorders such as osteogenesis imperfecta and Ehlers–Danlos syndrome [23]. This functional Sp1 binding site polymorphism has also been associated with multifactorial disorders, including osteoporotic fractures, variations in bone mineral density, osteoarthritis, myocardial infarction, lumbar disc disease, and stress urinary incontinence [25,26,27,28].

It has been proposed that a specific substitution within the intronic Sp1 binding site (referred to as a GRT substitution) enhances the binding affinity for the transcription factor Sp1, leading to an upregulation in COL1A1 gene expression [26]. Given the critical role of Type I collagen in the structural integrity of ligaments, the connection between the COL1A1 gene and anterior cruciate ligament (ACL) ruptures, a common and severe injury among athletes, is particularly noteworthy and warrants further investigation. Another common athlete injury that should also be taken into consideration for further studies is the rotator cuff tear, which is considered to be the main shoulder injury [29].

In their research, Khoschnau et al. discovered an association between the risk of cruciate ligament ruptures and shoulder dislocations and a specific polymorphism in the COL1A1 gene. Notably, individuals possessing the rare SS genotype, which had a 4% prevalence in their study, were less frequently observed in the injured group, suggesting a significantly lower risk of these soft tissue injuries. The study highlights the complex role of COL1A1, a gene encoding for a common collagen type found in bones, ligaments, and joint cartilage. Regulation of COL1A1 transcription varies, with one key regulatory site being the Sp1 transcription factor-binding site. Functional analysis revealed that the s allele of the Sp1 polymorphism, linked to osteoarthritis and osteoporosis, is associated with enhanced DNA-protein binding, increased transcription, and higher production of collagen type Iα1 mRNA and protein. The Sp1 polymorphism in the COLIA1 gene, found on chromosome 17, is autosomal and exhibits a recessive pattern of inheritance. It is distributed equally among women and men [24,30].

Type I collagen, composed of two α1 chains and one α2 chain encoded by genes on chromosomes 17 and 7, is known for its high tensile strength and resistance to most proteases [31]. While essential for providing mechanical strength to tissues—as seen in osteogenesis imperfecta [32]—its abnormal accumulation can contribute to fibrotic diseases, underscoring the delicate balance of collagen in tissue health and disease.

In the study led by Posthumus et al., three key findings emerged regarding ACL (anterior cruciate ligament) ruptures and genetic factors. First, the rare TT genotype of the COL1A1 Sp1 binding site polymorphism was significantly less common among individuals who experienced ACL ruptures, suggesting that this genotype might offer some protection against such injuries. Second, the study found that individuals with an ACL rupture were over four times more likely to have a family history of ligament injuries compared to control participants. Third, it was observed that the majority of ACL ruptures in their study group occurred due to non-contact events, and the distribution of genotypes in this subgroup was consistent with those in subgroups sustaining indirect and direct injuries [33].

The synthesis of data from independent studies made in South Africa [33,34] and Sweden [24] strengthens the idea of an association between a particular genotype and the risk of acute soft tissue ruptures. Confirmation of these findings could significantly impact clinical practice, as it suggests COL1A1 has a major role in maintaining the structural integrity of soft tissue.

COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI), a genetic disorder primarily characterized by fractures resulting from minimal or no trauma, presents with a spectrum of clinical manifestations. These manifestations range from perinatal lethality to severe skeletal deformities, mobility impairments, and notably shortened stature, extending to individuals who are nearly asymptomatic with only a mild predisposition to fractures. This spectrum also includes normal dentition, stature, and life expectancy. The disorder can also feature variable dentinogenesis imperfecta (DI) and, in adults, hearing loss. Fractures in COL1A1/2-OI, more commonly occurring in the extremities, are a hallmark of the condition. DI, when present, is typified by teeth that are gray or brown, possibly translucent, and prone to rapid wear and breakage. The classification of COL1A1/2-OI has been refined into four primary types, differentiated by their clinical and radiographic presentations. This categorization aids in the prognostication and management of affected individuals. These types are:

• Classic non-deforming OI with blue sclerae (formerly known as OI type I);
• Perinatally lethal OI (previously OI type II);
• Progressively deforming OI (formerly OI type III);
• Common variable OI with normal sclerae (formerly OI type IV).

The diagnosis of COL1A1/2-OI is confirmed in a proband through the identification of a heterozygous pathogenic or likely pathogenic variant in either the COL1A1 or COL1A2 gene, established via molecular genetic testing. This diagnostic approach underscores the genetic basis of the disorder and facilitates precise medical intervention, genetic counseling, and management strategies tailored to the specific type of OI diagnosed [35]. COL1A1 is a gene, usually with heightened expression in multiple cancer types, that can potentially influence key cellular processes like cell proliferation, metastasis, apoptosis, and cisplatin resistance. Its elevated expression correlates with a poorer prognosis in cancer patients, indicating its role in cancer progression. However, the specific function of COL1A1 as a cancer-promoting factor in particular tumors remains unclear. Furthermore, the expression levels and mechanisms of action of the COL1A1 protein vary across different tumor types [36,37].

COL1A1/2-Osteogenesis Imperfecta (COL1A1/2-OI) follows an autosomal dominant inheritance pattern. The likelihood of this condition being a simplex case (a single occurrence in a family) varies with the disease’s severity. About 60% of mild OI cases are simplex, whereas almost all cases of the more severe, progressively deforming, or perinatally lethal OI are simplex, often due to a de novo pathogenic variant or a variant inherited from a parent with somatic and/or germline mosaicism. Up to 16% of families may have parental somatic and/or germline mosaicism. Children of an individual with dominantly inherited COL1A1/2-OI have a 50% chance of inheriting the causative variant and potentially developing OI symptoms. Prenatal testing for at-risk pregnancies is possible through molecular genetic testing if the causative COL1A1 or COL1A2 variant is identified in a family member. Additionally, prenatal ultrasound examinations in experienced centers can help diagnose lethal and severe forms of OI before 20 weeks of gestation, with milder forms potentially identifiable later in pregnancy if fractures or deformities develop [35] (Table 1).

The COL5A1 gene is responsible for encoding the α1 chain of type V collagen, a minor fibrillar collagen present in ligaments, tendons, and various other tissues [38]. Type V collagen, which constitutes around 10% of the collagen in ligaments, plays a role in the structure and regulation of type I collagen fibril diameters by integrating into the core of type I collagen fibrils [39]. A significant finding relates to the CC genotype of the BstUI restriction fragment length polymorphism (RFLP) within the 3′-untranslated region (UTR) of the COL5A1 gene. This genotype was notably less common in individuals with chronic Achilles tendinopathy [40]. Given the compositional and structural similarities between tendons and ligaments, the COL5A1 gene emerges as a potential genetic risk factor for ACL (anterior cruciate ligament) ruptures [41].

Posthumus et al. reported that the CC genotype of the BstUI RFLP within the COL5A1 gene’s 3′-UTR was significantly underrepresented in female participants with ACL ruptures, but this was not observed in male participants. The study also found no association between the DpnII RFLP variant and ACL ruptures in either gender. Additionally, female participants with ACL ruptures reported a higher family history of ligament injuries, and this family history was also associated with the BstUI genotype in females. A novel discovery of this study was that female participants possessing the CC genotype of the COL5A1 BstUI RFLP appeared to have a reduced risk of ACL ruptures [42,43,44].

The Achilles tendon (AT) is recognized as one of the tendons most susceptible to rupture, accounting for approximately 20% of all large tendon injuries. This incidence is on the rise, as noted in studies [45,46]. The demographic most affected includes males, predominantly within the 40–50 age bracket. Such ruptures are significant, often marking the premature end of professional athletic careers. A notable characteristic of the AT is its midsection, which is the most common site for ruptures. This area, located 2 to 6 cm proximal to its insertion point, is particularly vulnerable due to its relatively poor vascularization [45]. Typically, the rupture is preceded by a degenerative process within the tendon. Eriksen et al. identified an increased presence of type III collagen at the rupture site, which they suggest may be a result of prior microtraumas and associated healing processes that reduce the tendon’s tensile strength. These compromised tissue conditions could potentially hinder the healing process following a rupture [47].

The COL5A1 gene encodes the proα1(V) chain, essential in the assembly of type V collagen trimers; this collagen, being part of the fibrillar collagen subfamily, is predominantly found in the a1(V)2a2(V) isoform. It frequently co-assembles with type I collagen, forming heterotypic type I/V fibrils in tissues, including tendons, ligaments, bone, sclera, and cornea [48,49]. While the exact biological functions of type V collagen, especially in regulating type I collagen fibril diameter, are not fully understood, its significance in the development of connective tissues is well documented [50]. Notably, mutations in COL5A1 are linked to Ehlers–Danlos syndrome, characterized by the laxity and fragility of soft connective tissues [51]. Hence, variants in the COL5A1 gene, as identified in a South African study [52], could predispose individuals to increased risks of tendon or ligament injuries.

This association is further supported by Mokone et al. [52], who identified a significant correlation between the allelic variant marker rs12722 (BstUI RFLP) but not rs13946 (DpnII RFLP) in the 3′-UTR of the COL5A1 gene and symptomatic chronic Achilles tendinopathy in a South African cohort. Furthermore, September et al. confirmed the association of the BstUI RFLP (rs12722) with chronic Achilles tendinopathy in an Australian white population, pinpointing a critical region within the 3′-UTR of the COL5A1 gene that may increase susceptibility to this condition. These findings underscore the complex etiology of chronic Achilles tendinopathy, involving both genetic and non-genetic factors, and highlight a specific interval within the COL5A1 3′-UTR as a predisposing factor in both Australian and South African populations. Consequently, clinicians treating chronic Achilles tendinopathy should consider the potential role of genetic factors in assessing the risk of developing this injury [40,52] (Table 2).

Collagen type XI alpha 1 (COL11A1) is a component of type XI collagen, playing a vital role in bone development and collagen fiber assembly. Notably, COL11A1 expression is frequently upregulated in various cancers, with elevated levels correlating with adverse clinical outcomes, including poor survival, chemoresistance, and recurrence in numerous solid cancers. This upregulation suggests that COL11A1 contributes to tumor cell aggressiveness through multiple mechanisms. COL11A1, encoding one of the three alpha chains of type XI collagen, is primarily expressed in cartilage. In this tissue, it forms a heterotrimer with COL11A2 and COL2A1, essential for the assembly of type XI collagen [53,54]. Genetic mutations in the COL11A1 gene are linked to type II Stickler syndrome and Marshall syndrome. These autosomal dominant disorders are characterized by facial dysmorphism, myopia, and hearing loss [55,56]. Additionally, a specific single-nucleotide polymorphism in the COL11A1 gene has been associated with an increased risk of lumbar disc herniation [57]. In mice, a point mutation in the COL11A1 gene leads to the lethal chondrodysplasia phenotype, characterized by severe skeletal defects [58].

Recent research has elucidated that COL11A1, along with COL11A2 and the product of the COL2A1 gene, previously known as COL11A3, forms a heterotrimeric complex of collagen type XI [59,60]. This complex is crucial in regulating the fibrillogenesis of collagen types I and II. Besides its role in collagen formation, COL11A1 interacts with various other proteins, including ECM proteoglycans (e.g., biglycan, fibromodulin, and chondroadherin), ECM components (e.g., Thrombospondin-1, matrilin-1/3, chondrocalcin), and other collagen types (e.g., II, XI, XIV, XII, IX). Oncostatin M (OSM), an inflammatory cytokine, binds to collagen type XI in matrices derived from MDA-MB-231 breast cancer cells, further illustrating COL11A1’s diverse interactions. Additionally, COL11A1 may form a unique heterotrimer with COL5A1 and COL5A2, although the precise stoichiometry of this association remains uncertain. Several studies have indicated that COL11A1, as well as COL11A2, can be associated with early-onset OA [61]. In a study conducted by Xu et al., they revealed that in homozygous cho/cho mice, the absence of the protein product of the Col11a1 gene is confirmed through Western blotting and immunohistochemical analysis. Given that type XI collagen is composed of three distinct polypeptide chains (α1, α2, and α3), the formation of normal type XI collagen is likely hindered in the absence of the α1 (XI) chain. This deficiency is posited to contribute to the cho phenotype, characterized by the lack of normal type XI collagen in cartilage. Furthermore, the cartilage in these mice is marked by unusually thick type II collagen fibrils. These findings indicate that a reduced level of type XI collagen in cartilage may be a primary factor in the onset of osteoarthritis (OA) [62]. This multifaceted role of COL11A1 in both normal physiological processes and pathologies like cancer and connective tissue disorders highlights its significance in cellular and molecular biology [63] (Table 2).