Fibromodulin-deficient (Fmod −/−) mice show abnormalities in tail and Achilles tendon. Histology revealed reduced number and disorganized fiber bundles with reduced number of cells in mutant tail tendon. Mutant mice also showed reduction in endotenon tissue. In WT tail tendon, the molar ratio of Lum : Fmod is 1 : 3. Fmod is expressed in collagen fibrils of tendon and Lum in peritendon area in tail and Achilles tendon. Lum protein level increased 4-fold in Fmod −/− tail tendon, whereas Dcn level did not change. Achilles tendon from fibromodulin-deficient mice showed collagen fibrils with irregular and rough outlines, altered fibril diameters, and disrupted fibril diameter frequency distribution across the tendon.
Fmod −/− mouse was generated. Mutant mice exhibit subtle phenotype, breed normally, and live normal life span.
Lum −/− mouse was generated. Mutants have thicker collagen fibrils in skin and cornea and develop opacification. Mice show skin laxity resembling EDS, type I; OMIM: 130000.
Mice deficient in SLRPs (Lum −/−, Fmod −/−, and Lum −/−/Fmod −/−) show disruptions in collagen fibrillogenesis. Protein expression showed that Lum functions during early stages in fibrillogenesis, while Fmod functions throughout this period with a more prominent role in the regulation at later stages. The codistribution of Lum and Fmod was present throughout the tendon matrix at P10. Structurally, three distinct abnormalities were observed due to their deficiency: the premature heterogeneity of fibril diameter at P4 in Lum −/−/Fmod −/− tendon in contrast to WT; abnormally large number of small diameter fibrils at later stages of development best seen at 3 months in Fmod −/− and Fmod −/−/Lum −/− mice; all the three mutants had fibrils with irregular profiles and contours, indicative of abnormal defective lateral fusion and rearrangement. At 1–3 months, Fmod −/− and Lum −/−/Fmod −/− mice had large number of abnormal “cauliflower-like” tendon fibrils with Dbl-KO fibrils showing the most severe phenotype. In contrast, Lum −/− tendons contained fibrils only slightly irregular in profile and contour.
The double homozygote mutant mice Lum −/−/Fmod −/− were produced by Het Het crossings and present mouse model for human EDS, type I; OMIM: 130000.
Mice lacking both lumican and fibromodulin exhibit knee dysmorphogenesis, and extreme tendon weakness is the cause for joint laxity in mutant. Fmod deficiency alone leads to significant reduction in tendon stiffness but further loss in stiffness is demonstrated by the loss of Lum in a dose-dependent way. A disproportionate increase in small-diameter collagen fibrils in the Fmod −/− mice may be the cause of tendon weakness indicating that Fmod aids in fibril maturation. Dbl-KO mice display a 2-fold increase in knee joint deflection indicating increased joint laxity and show medial misaligned patella and secondary patellar groove in 65% cases. Dbl-KO mice show collagen fibrils with “cauliflower”-like contours in TEM cross-sections, indicating abnormal lateral growth in fibrils.
Double homozygote mutants Lum −/−/Fmod −/− have smaller-sized body and develop age-dependent OA. The mice mimic human disease model: EDS, type I; OMIM: 130000.
Dcn
tm1Ioz: decorin; targeted mutation 1, Renato V Iozzo Allele type: T (KO) Mut: insertion Syn: Dcn −
Decorin-deficient mice exhibit abnormal collagen fibrillogenesis in tail tendon and a decrease in collagen-associated proteoglycans. Using TEM analysis, tendon fibrils showed irregular and ragged outlines in cross-sections in Dcn −/− mice compared to more uniform fibrils in Dcn +/+ mice. The frequency distribution of fibril diameter across tendon was altered in Dcn −/− mice.
Dcn −/− mouse was generated which exhibits skin fragility and aberrant collagen fibrillogenesis and is a model for EDS, progeroid form; OMIM: 130070.
Periodontal ligament is adversely affected by decorin deficiency in mouse. Using SEM, Dcn −/− molar PDL showed collagen fibers wider in diameter and more randomly arranged than WT. In TEM cross-sections of Dcn −/− molar PDL, the collagen fibers were irregularly shaped and were more randomly arranged. There was more heterogeneity in collagen fibers which constituted very large-diameter fibers with many very small-sized fibers in PDL in Dcn −/− mice. Molar PDL showed hypercellularity in mutants. Ectopic overexpression of exogenous Dcn, in PDL fibroblast cultures, suppressed cell growth suggesting decorin as a negative regulator of cell proliferation in PDL fibroblasts.
Decorin deficiency alters structure and biomechanical properties of tendon during development. Bgn expression increased substantially in Dcn-deficient tendons suggesting a potential functional compensation. FDL tendon of Dcn −/− mice was analyzed at P1, 10, 60, and 90. Fibrils with irregular contour and lateral fusions were present at P10–P90. Besides FDL tendon, tail tendon exhibited severely altered fibril structure at the age of 7.5 months (Figure 3), also supporting that the defect in mutant mice is tendon specific. FDL tendon of mature mutant mice (P150) indicated a decrease in strength and stiffness.
Patellar tendon retrieved from mature Dcn −/−, Dcn +/−, and Dcn +/+ mice contains a different content of decorin and differs in its properties. Viscoelastic, tensile dynamic modulus increased in the Dcn +/− tendons as compared to Dcn +/+. There was a reduction in total collagen in Dcn +/− tendon as compared to WT, though Dcn −/− and Dcn +/+ tendons did not differ. Mean fibril diameter in Dcn −/− was smaller than WT and Dcn +/−. The fibril diameter distribution histogram from Dcn −/− tendons demonstrated an increase in number of fibrils with smaller diameter. In TEM cross-sections, there was minor difference in the contour of fibrils in patellar tendon between different genotypes (unlike tail tendon). These results suggest that Dcn plays a role in tendon viscoelasticity that cannot be completely explained by its role in collagen fibrillogenesis. Dcn −/− tendons did not differ from WT in any tensile elastic parameter. In addition, no differences were seen in Dcn +/− compared to WT tendons in any of the elastic parameters. No differences were seen between genotypes for compressive properties. In the viscoelastic properties, Dcn genotype did not significantly affect phase shift that is a measure of the viscoelastic damping of the material. It is possible that the relationship between collagen, SLRPs, and water is more complex than evaluated here.
Injured Dcn −/− Achilles tendons heal better than WT tendons. Four-month-old Dcn −/− mice underwent a bilateral, centralized, full-thickness, partial-width injury in Achilles, and animals were sacrificed at 3 weeks after injury. Uninjured Dcn −/− tendons had increased tendon cross-section area, decreased linear modulus, increased tan , and decreased compared to WT, whereas injured Dcn −/− tendons had decreased tendon cross-section area, increased linear modulus, decreased tan , and increased compared to WT. Deletion of Dcn during tendon healing may reduce scarring and improve collagen fibrillogenesis by allowing the formation of more mechanically stable collagen fibrils.
Dse
tm1Mmac: dermatan sulfate epimerase; targeted mutation 1, Marco Maccarana Allele type: T (KO) Mut: insertion (IGD) Syn: Dse −
The lack of Dse affects the epimerization of glucuronic acid to iduronic acid in glycosaminoglycans (GAGs) and affects the tendon properties. In tail tendon, in Dse −/− mice, the frequency distribution of collagen fibril diameter shifted towards larger-diameter fibrils, whereas in Achilles tendon, there were subtle changes compared to WT counterparts.
Dse −/− mouse was generated. Mice showed decreased litter size, birth length, and weight. Mice showed decreased skin tensile strength and thicker collagen fibrils.
The SLRPs Lum, Fmod, and Dcn coordinately regulate the fibrillar organization of collagen in the PDL. These three SLRPs coexpressed with type I collagen in gingival and PDL. Lum −/− mice showed PDL phenotype different from WT and other SLRP mutants. In longitudinal sections, thin fiber bundles predominated. The fibers showed uneven outlines with numerous thin fibers projecting from the bundles. Individual collagen fibrils had irregular cross-sections and showed heterogeneity. Overall the fibrils diameter was smaller than other mutants and WT mice. Interfibrillar spaces varied. Fmod −/− PDL displayed collagen fiber bundles heterogeneous in thickness along the length. In contrast to Lum −/− mice, Fmod −/− PDL showed a relative increase in the number of thick fiber bundles. It was difficult to trace the fibril bundles from tooth to bone surface. Like Lum −/− but unlike WT mice, the spaces between the fibril bundles were not evenly distributed throughout the ligament. Individual collagen fibrils displayed enlarged cross-sectional areas, but with heterogeneity in the fibrils diameter, with small fibrils dispersed between larger ones. The inter-fibrils spaces were variable and enlarged. Fibril outline was uneven as compared to WT. Fmod −/−/Lum −/− PDL contained some of the attributes of both single knockout mice. In Dcn −/− mice, the PDL collagen fiber bundles showed the typical 45° angle orientation seen in WT but the fiber bundles were heterogeneous in size with increased spaces between the bundles. The bundles were wider as compared to other three mutants and nonuniform in shape. Like in other mutants, the fibril bundles displayed very thin filamentous structures branching out from the main bundles. The fibrils were heterogeneous in size, with numerous small diameter fibrils among large diameter fibrils. The fibrils also displayed slightly uneven outlines as compared with WT. The inter-fibrils spacing was more variable as compared with WT.
Col1a1
mov13/+ mouse was generated [43], Col1a1 mov13/mov13 was reported to be lethal [44], and Col1a1 mov13/+ exhibited connective tissue defects and progressive hearing loss [45] and is a model for osteogenesis imperfecta type I; OMIM: 166200
Alteration in matrix proteins in tail tendon affects quasilinear viscoelastic properties. Uniaxial tensile stress-relaxation experiments were performed on tail tendon fascicles taken from mice at different developmental age and genotype groups: 8-week Dcn −/−, 8-week Col1a1 mov13/+ (50% reduced type I collagen), 8-week control mice and 3-week control mice. The viscoelastic properties demonstrated a larger and faster stress relaxation for decorin-deficient mice and a smaller and slower stress relaxation for 3-week control mice (i.e., tendons with increased proteoglycans and associated GAGs). The elastic parameter in 8-week control group (tendon with more collagen but lesser proteoglycan than 3-week) was significantly greater than in the mice with reduced collagen (Col1a1 mov13/+) and 3-week control mice.
Viscoelasticity of tail tendon fascicle is affected by Dcn content but not by collagen alterations. Mechanical properties of tail tendon fascicles were assessed in different genotype and age group of mice: 8-week Dcn −/− (mouse lacking Dcn), 8-week Col1a1 mov13/+ (mouse with 50% reduction in Col I), 8-week Col1a1tm1Jae/Col1a1tm1Jae (Col I accumulation in soft tissues), 8-week control (normal mature mouse), and 3-week control mice (immature mouse). Uniaxial tensile ramp to failure experiments were performed on tail tendon fascicles at two strain rates, 0.5%/s and 50%/s. Mutations in Col I (Col1a1 mov13/+ or Col1a1 tm1Jae/Col1a1tm1Jae) led to reduced failure load and stiffness with no changes in failure stress, modulus, or strain rate sensitivity. Dcn-deficient fascicles had similar elastic properties as normal control fascicles, but with reduced strain rate sensitivity. Fascicles from immature mice (3-week control with increased Dcn content compared to adult fascicles) had inferior elastic properties but higher strain rate sensitivity. It is evident that the tendon viscoelasticity is affected by proteoglycan Dcn content and not by collagen alterations.
In a large multivariate model, glycosaminoglycan (GAG) content is the largest predictor of mechanical properties. Tendon fascicle structure-function relationship was established in transgenic models using multiple regression models. Relative contributions of seven different structural and compositional variables were used in predicting tissue mechanical properties through the use of multiple regression statistical models. Structural, biochemical, and mechanical analyses were performed on tail tendon fascicles from different groups of transgenic mice as shown in the last reference [46]. GAG content was observed to be the strongest predictor of mechanical properties. GAG content was also well correlated with collagen content and mean collagen fibril diameter. Collagen fibril area fraction was a significant predictor only of material properties.
Lack of biglycan adversely affects the mechanical property of the healing bone insertion site of the patellar tendon (PT) fibers. For that, the authors compared 12-week-old hemizygous Bgn −/0 and WT male mice, and the midsubstance of the PTs of the mice was surgically removed (a 3 mm gap injury model), and the mice were allowed for a cage activity after surgery for 4 weeks. The tensile test was performed for the healing patellar tendon-tibia complex. Collagen fibril diameter distribution was disturbed in mutant mice. At the beginning of surgery, frequency distribution of collagen fibril diameter was towards left (smaller diameter fibrils) in Bgn −/0 as compared to WT tendon. At 4 weeks after surgery, the collagen fibril diameter distribution was towards right (larger diameter fibrils) in Bgn −/0 as compared to 4 weeks after surgery in WT controls.
N/A Note that biglycan is located on X chromosome. Male biglycan deficient is represented as hemizygote Bgn −/0, whereas female homozygote is represented as Bgn −/−
Lack of biglycan compromises the integrity of periodontal tissue. IHC of SLRPs indicated that Bgn is expressed in PDL, alveolar bone (AB), at the AB-PDL, and cementum-PDL attachment sites in WT mice. Histomorphometric analysis of XCT images of periodontal tissues of 8-week-old mice was performed. Deeper AB resorption pits within interdental region of Bgn-KO specimens were compared to WT which showed the significant difference in PDL space of Bgn-KO (93 mm3) and WT (74 mm3) mice. Cementum-PDL-AB complex exhibiting higher PDL space in Bgn-KO mice does compromise the integrity of periodontal tissue.
XCT analysis showed higher volumes of enamel, root, and larger tooth size in Bgn-KO than WT mice.
Abnormal collagen fibrils in tendons of Bgn/Fmod-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. Collagen fibrils in tendons from Dbl-KO mice are structurally and mechanically altered resulting in unstable joints. The mice progressively develop gait impairment, tendon ectopic ossification (EO), and severe premature OA. Daily forced running of Bgn −/0/Fmod −/− mice for a month increased EO and resulted in severe OA. Radiographs of 3-month-old mice revealed EO in the Achilles, patellar, and quadriceps tendons of the knee in all the mutants (Bgn-KO, Fmod-KO, and Dbl-KO). Quadriceps tendon showed irregular collagen fibrils in cross-sections in all the mutants at the age of 3 months. Stiffness reduced significantly in patellar tendon in Dbl-KO at the age of 1 month before tendon begins to ossify.
Bgn and Fmod double deficient mice exhibit premature OA and predisposition to OA. The Dbl-KO mouse represents a model for spontaneous OA, early onset and rapid progression of OA.
Mice deficient in biglycan and fibromodulin (Bgn −/0/Fmod −/−) show patellar tendon defects. Gross morphology of patellar tendon at the age of 4 months showed abnormal translucent color in Bgn −/0/Fmod −/− mice, whereas tendon was white in color in WT mice. H&E of longitudinal sections of P6 tendon from Dbl-KO was more thinner, more cellular, and with more gaps among collagen fibers. Under polarized light, these exhibited disorganized collagen fibrils. CT of knees of 2-month and 5-month Bgn −/0/Fmod −/− mice showed ectopic ossicles formed in patellar tendons.
Mice deficient in biglycan and fibromodulin develop ectopic ossification (EO) in tendon with aging. At the age of 3 months, Bgn-KO, Fmod-KO, and Dbl-KO displayed torn cruciate ligaments and EO in their quadriceps tendon, menisci, cruciate, and patellar ligaments, and the phenotype was least severe in Fmod-KO, intermediate in Bgn-KO, and the most severe in Dbl-KO. The EO progressed with age from 3 months to 9 months. In Dbl-KO mice subjected to moderate treadmill exercise, the EO was decreased compared to “unexercised” mice. Male Bgn −/0/Fmod −/− mice had more EO compared to female Bgn −/−/Fmod −/− mice but both had decreased EO after the forced moderate treadmill exercise regime. Dbl-KO and Bgn-KO mice exhibited reduced ability to maintain grip on a rotating cylinder in rotarod performance test. At early stage of mineralization of tenocytes (in Bgn-KO or Dbl-KO) in mutant mice, the tenocytes lost their elongated fibroblast-like phenotype and acquired a rounded chondrocyte-like phenotype. With time, the intercellular spaces became completely mineralized, but the mineralization remained confined to the fibrocartilage area within the tendon in mutants. The mineralization process was also observed in the cruciate ligament of 3-month Bgn-KO and Dbl-KO.
Collagen fibrillogenesis is altered in tail tendon of Bgn −/0 and Dcn −/− mice as demonstrated by collagen fibril morphology with frequent occurrence of irregular cross-sectional profile with ragged or notched contour. The range of collagen fibril diameter increased in mutant mice as compared to WT mice.
Bgn −/0, Dcn −/−, and Bgn −/0/Dcn −/− mice showed varied defects in dermal and bone collagen fibrils. The Bgn −/0/Dcn −/− mice mimic rare progeroid variant of EDS; OMIM: 130070.
Tendons are tailored according to their specific location and function. Mechanical properties of tail tendon fascicles, patellar tendon (PT), and FDL tendon, each differing in their in vivo loading environment from one another, were characterized in 8–10-week-old Bgn- and Dcn-deficient mice. No change in mechanical properties was observed for tail tendon fascicles due to either proteoglycan’s deficiency. The loss of Dcn caused an increase in modulus and stress relaxation but had little effect on FDL. Conversely, the loss of Bgn did not affect PT but caused a reduction in maximum stress and modulus of the FDL.
Decorin deficiency protects aged tendons. Multiple properties of patellar tendon (PT) from mature (age, 150 days) and aged mice (age, 570 days) were studied in Dcn-KO and Bgn-KO mice. Aged WT PT exhibited inferior properties as compared to mature WT and showed deteriorating viscoelastic properties, reduced dynamic modulus, decreased cellularity, alterations in tenocyte shape, and reduced collagen fibers alignment. Fibril diameter distribution indicated an altered distribution in aged tendons with an increase of large-diameter fibrils. Dcn-deficient tendons exhibited decreased effects of aging compared to the other genotypes (Bgn-KO or WT). The amelioration of the functional deficits seen in the absence of Dcn in aged tendons was associated with altered tendon fibril structure which was comparable to mature WT tendon.
Decorin and biglycan contribute to tendon’s response to load, in particular with realignment of collagen fibers. Isolated supraspinatus tendon (SSTs) from Bgn- and Dcn-deficient mice, at three different age groups (90 days, 300 days, and 570 days), were tested in tension. Changes in realignment in WT tendons showed a decreased response to load with aging. Tendons at 300 days and 570 days do not realign their collagen fibers until the linear region, a later response than 90-day tendons. This result in WT tendon midsubstance is indicative of a breakdown of the structural organization of tendon over time. The proteoglycan-deficient tendons showed altered mechanical properties with age, predominantly at the insertion site. However, changes in realignment throughout age were not found in the midsubstance of the Bgn-deficient tendons or at the insertion of Dcn-deficient tendons. Lack of these proteoglycans may shield the tendon from deteriorating effects. Changes in mechanical properties did not occur in concert with changes in collagen fiber realignment, suggesting that typical mechanical property measurements alone are not sufficient to describe how structural alterations affect tendon’s response to load.
ASPN: asporin Strategy: knockdown Syn: PLAP-1 (PDL-associated protein 1)
Knockdown of ASPN transcript levels by RNAi enhanced Bmp-2-induced differentiation of PDL cells. Overexpression of asporin in mouse PDL-derived clone cells inhibited both naturally and BMP-2-induced mineralization of the PDL cells, whereas knockdown of asporin transcript levels by RNAi enhanced Bmp-2-induced differentiation of PDL cells.
MicroRNAs, miR-21, and miR-101 regulate asporin/PLAP-1 expression in PDL cells. Bioinformatic analysis predicted miRNAs that potentially regulate the gene expression of asporin. Dual luciferase reporter assay and qRT-PCR showed the effects of miR-21 and miR-101 on asporin gene expression. The results indicated that miR-21 and miR-101 target asporin to regulate its expression during osteogenic differentiation of PDL cells.
Thbs2
tm1Bst: thrombospondin 2; targeted mutation 1, Paul Bornstein Allele type: T (KO) Mut: insertion (IGD) Syn: Tsp2 −
Lack of thrombospondin 2 results in connective tissue abnormalities associated with disordered collagen fibrillogenesis. Tail tendon exhibited abnormalities in Thbs2 −/− mouse. The mutants show poor control of tail movement, when held by the tip of the tail, Thbs2 −/− mice had difficulty in pulling their body up to the base of tail indicating that the mutant mice had abnormalities in tail tendon and in intervertebral ligaments. Tail tendon exhibited abnormalities in collagen fibrils presenting larger diameters and uneven contours in mutant mice (large fibril diameter range in mutant versus WT was in the order of 400 nm versus 250 nm, resp.).
Thbs2 −/− mice were generated and showed reduced skin strength, abnormal collagen fibrillogenesis, bone and bleeding defects, and increased blood vessels.
Thrombospondin 2 modulates cell-matrix interaction during postnatal development of tendon. Developing hind limb flexor muscle tendon showed abnormalities in fibroblast-collagen fibril interaction in Thbs2 −/− mice. During tendon development, P4 and P8 tendons show fibroblastic extracytoplasmic channels where fibrils assemble first and then coalesce into small fibers. The “compartmentalization of fibrils assembly” as well as “of coalescence” was disrupted in developing tendon in Thbs2 −/− mice.
Thbs2 −/− mice showed abnormal skin collagen fibrils. The mutants also exhibited increased vascular density in skin.
Spp1 plays role in tendon remodeling after denervation-induced mechanical stress deprivation. Six-week-old males demonstrated mechanical stress deprivation in quadriceps femoris muscle after femoral nerve denervation. Patellar tendon underwent dynamic remodeling as evidenced by collagen fibril degradation. Transient upregulation of SPP1 expression was observed in early phase followed by induction of MMP13 during patellar tendon remodeling in WT animals, the later involved degradation of collagen. MMP-13 gene expression increased 20.7-fold at day 14 after stress deprivation in WT mice and 4.1-fold in mutants. Thus Spp1 plays a crucial role in conveying the effect of denervation-induced mechanical stress deprivation to the tendon fibroblasts to degrade ECM by regulating MMP-13 expression.
Sparc
tm1Hwe: secreted protein acidic and rich in cysteine; targeted mutation 1, Chin Chen Howe Allele type: T (KO) Mut: insertion Syn: SP −, Osteonectin −, ON −, Sparc −
N/A
Sparc −/− mice were generated. Mutants develop opacities in posterior cortex of eye as early as 1.5 month after birth indicating that Sparc is essential for maintenance of lens transparency.
Sparc plays a role in controlling collagen content in PDL and is required for PDL homeostasis. Sparc expression, evaluated at 4 time points of aging, In the highest levels were at the age of 1 month and >18 months and reduced levels at 4 months and 6 months in mouse PDL. Absence of Sparc influenced cellular and fibrillar collagen content in PDL. The greatest differences in cell number and in collagen content between Sparc −/− and WT PDL coincided with ages at which levels of Sparc expression were the highest in WT at 1 and >18 months.
Sparc protects collagen content in PDL and alveolar bone in experimental periodontal disease. Periodontal disease was induced in 4-month WT and Sparc −/− mice by LPS injections between first and second molars. In LPS-injected sites, PDL of Sparc-deficient mice showed more disorganization compared to WT. Substantial degradation was shown in the gingival tissues in Sparc −/− mice. Collagen loss, induced by LPS as determined by “total collagen volume fraction” and “thick collagen volume fraction,” was more extensive in Sparc −/− mice than WT. In PBS-injected sites, Sharpey’s fibers were thicker in WT but were more in number in mutants.
CT analysis of Sparc-deficient maxillae injected with lipopolysaccharide (LPS) demonstrated reduced alveolar bone volume fraction compared to WT mice.
Postn
tm1Sjc: periostin, osteoblast specific factor; targeted mutation 1, Simon J. Conway Allele type: T (R) Mut: insertion (IGD) Syn: Peri lacZ, Postn −
Periostin is required for the maintenance of PDL integrity in response to mechanical stress. Postn −/− mice showed the formation of dental alveolar defects and severe incisor enamel defects by 3 months. Placing the Postn −/− mice on a soft diet alleviated mechanical strain on PDL, which resulted in a partial rescue of both the enamel and periodontal disease-like phenotypes. It was concluded that a healthy PDL is required for normal amelogenesis and Postn is required for maintaining the integrity of the PDL in response to mechanical stress. Postn showed higher expression in PDL than in other tissues in 4-week WT mouse, and Postn −/− mice showed abnormal PDL morphology at that age. Fully erupted molars displayed widening of the Postn −/− PDL. By the age of 3 months, Postn −/− mice develop an early-onset periodontal disease-like phenotype resulting from abnormalities in PDL.
Postn −/− mouse was generated, 14% mutants die before weaning, and the rest were runted. Trabecular bone in adult is sparse. Female cyclicity is abnormal. The Postn −/− represents periodontitis, aggressive 2, OMIM: 608526.
Periostin is essential for the integrity and function of the PDL during occlusal loading. PDL integrity is required for periodontium structure function. Before tooth eruption, PDL is normal in Postn −/− mice. After eruption, sustainment of occlusal load became evident, and the lack of PDL integrity became obvious in mutants leading to alveolar bone defects and malformed incisors. Severe periodontal defects were observed in mutants after tooth eruption. With time, periodontium deteriorates and widening of PDL persisted in mutants. The removal of masticatory forces in mutants, by using occlusal hypofunction model, rescued the periodontal defects.
Alveolar bone, cementum, and enamel are affected adversely in Postn −/− mouse. The mutant mouse represents human disease: periodontitis, aggressive 2, OMIM: 608526.
Periostin is an ECM protein required for the eruption of incisors in mice. Remodeling of PDL of incisors is defective in Postn −/− mice. Continuous eruption of the incisors, by constant formation of dentin and enamel in mouse, is accompanied by the formation of a shear zone within PDL at which the PDL is remodeled continuously. The remodeling shear zone at which periostin is expressed in WT is shown to be absent in 12-week Postn −/− mice (Figure 4).
Postn −/− mouse was generated. Mutants exhibit abnormal ameloblast, dentin, and enamel morphology, have short incisors assessed at 6 weeks, and show abnormal tooth eruption.
Postn
tm1Jmol: periostin, osteoblast specific factor; targeted mutation 1, Jeffery D. Molkentin Allele type: T (KO) Mut: insertion (IGD) Syn: Pn−, periostin−, Postn −
N/A
Postn −/− mouse was generated and revealed that periostin regulates cardiac hypertrophic response, interstitial fibrosis, ventricular remodeling, and myocardial infarction.
Periostin regulates collagen cross-linking in tendon. Periostin-deficient mice show decreased cross-linking in tendon. IHC and immunogold TEM demonstrated that periostin colocalizes with collagen type I in tendon. Using differential scanning calorimetry on samples from 3-month-old mice, lower denaturation temperatures for Postn −/− tendon, indicated reduced collagen cross-linking as compared to WT tendon.
Postn −/− mice exhibited skin and atrioventricular connective tissue defects.
Postn: periostin Species: Mus musculus Origin: not available Syn: pstn −
Complete deficiency of periostin does not appear to affect failure load in intact as well as in healing Achilles tendon, whereas partial deficiency does. Role of periostin was investigated on intact and healing Achilles tendon using mouse deleted in Postn/Pstn gene. Achilles tendon from 10-week-old WT, Postn −/−, and Postn +/− was transected and repaired. After 14 days of healing, failure load values in WT tendon were significantly higher than Postn +/− but nonsignificantly different from Postn −/− tendon. Similar results were observed in intact tendon among the three genotypes. Authors concluded that there must be some compensatory mechanism in homozygote mutant tendon in which failure load values are more close to WT.
TNC (Homo sapiens): tenascin C Loc: Chr 9q33 COL27A1 (Homo sapiens): collagen, type XXVII, α1 Loc: Chr 9q32
Genetic variants within TNC gene and COL27A1 genes on human chr9q32-33 are involved in Achilles tendinopathy (AT). COL27A1 gene has been mapped to chromosome 9q32-33, 708 kbp upstream of TNC. In a case control study, 339 healthy control participants and 179 participants clinically diagnosed with AT from South Africa and Australia, were genotyped for variants: rs4143245, rs1249744, rs753085, rs946053 (COL27A1) and rs13321, rs2104772, and rs1330363 (TNC). The rs2104772 and rs1330363 variants within TNC showed a significant allele association with AT. The GCA haplotype (rs946053-rs13321-rs2104772) occurred significantly more frequently in 10 AT participants compared to control. The haplotype (i) rs946053 (G > T) lays within a putative c-Myc transcription factor binding site which is eliminated in the presence of the T-allele; (ii) rs13321 (G > C) lays within a putative GATA transcription factor binding site, and putative splicing regulatory elements are found 7 and 15 bp down stream of this SNP.
TNC (Homo sapiens): tenascin C Loc: Chr 9q33 Mut: guanine-thymine dinucleotide (GT) repeat polymorphism in intron 17
The GT repeats polymorphism within TNC gene is associated with Achilles tendon injuries. In a case control study, 114 physically active white subjects with symptoms of Achilles tendon injury and 127 asymptomatic physically active white control subjects were genotyped for GT repeats within TNC gene. Allele containing 12 and 14 GT repeats was overrepresented in subjects with tendon injuries, while the allele containing 13 and 17 GT repeats was underrepresented. Subjects with variants of TNC gene for 12 and 14 GT repeats had 6-fold risk of developing Achilles tendon injuries.
Tnxb
tm1Jbrs: tenascin XB; targeted mutation 1, James Bristow Allele type: T (R) Mut: insertion (IGD) Syn: Tnx-KO, Tnxb −
N/A
Tnxb −/− mouse were generated, and the skin showed hyperextensibility, failure of fibroblast to deposit collagen I. The mutant mouse is modelled for human EDS, autosomal recessive; OMIM: 606408.
Tnx deficiency alters properties of force transmission pathways of muscle, the later being the part of myotendinous or myofascial pathways, and directly affects muscle function in Tnxb −/− mice.
Tenomodulin is a regulator of tenocyte proliferation and is involved in collagen fibril maturation. Tnmd-deficient Achilles tendon exhibits lower cell density at 1 month and 6 months of age. Patellaris and Achilles tendon show reduced cell densities in 2 weeks but not in newborn or at P7 Tnmd −/− mice. Reduction in cell proliferation rate, in mutant patellaris tendon, was demonstrated in newborn. This deficit in cell proliferation rate caused lower cell density at P14 and adult tendons. At 6 months mutant tendons had a greater heterogeneity of collagen fibrils with more thick fibrils and fibrils with uneven surfaces.
Tnmd −/− mouse was generated. Mice lacking both Tnmd and ChM-I (Tnmd −/−/Lect1 −/−) had normal retinal vascularization and neovascularization.
TNMD (Homo sapiens) Knockdown of all the three isoforms of TNMD by RNAi assay
Tenomodulin regulates cell proliferation. Targeting TNMD by RNAi assay (with siRNA against human TNMD exon 5) in human flexor carpi radialis (FCR) cells knocked down all the three human TNMD isoforms. The knockdown of FCR cells showed reduced cell proliferation and upregulated expression of myostatin and scleraxis.
Lack of Cd44 antigen leads to improved healing in injured patellar tendon. The study was conducted in a patellar injury model of 12-week-old Cd44 −/− mice. The material properties of the healing Cd44 −/− tendon were superior to WT at 3 weeks and 6 weeks after injury. The matrix components and cytokines, beneficial to healing, increased in mutant tendon. Cross-sectional area of tendon was significantly reduced in mutant tendon at 3 weeks and 6 weeks after injury.
Adamts5 Δexon2: a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5; Exon2 deleted Allele type: T (KO) Mut: insertion (IGD) Syn: Adamts5 −
N/A
Adamts5 −/− mouse was generated. Mice were resistant to destabilization of the medial meniscus-induced OA-like lesions and to the associated mechanical allodynia.
Aggrecan turnover is Adamts5-mediated, and lack of Adamts5 results in adverse effects on structure and function of tendon and enthesis. FDL tendon (a single fascicle lacking prominent insertion site) of 12-week-old Adamts5 −/− mice showed structural abnormalities and decreased material properties as a result of accumulation of aggrecan in the pericellular matrix of tendon fibroblasts. In Achilles tendon (a multifascicles tendon with defined insertion of tendon fibers), Adamts5 −/− mice exhibited higher tensile modulus and weak enthesis in mutants.
Prg4
tm1Mawa: proteoglycan 4; targeted mutation 1, Matthew Warman Allele type: T (KO) Mut: insertion (IGD) Syn: Lubricin −
Lack of Prg4 causes abnormal calcification of tendon and sheath involved in ankle joints leading to precocious joint failure. The morphologic changes in 7-month-old Prg4 −/− mice was compared to Prg4 +/− mice. Homozygous mutants demonstrated abnormal calcification of tendon sheaths of tibialis anterior that surrounds the ankle joint. Absence of Prg4 within the tendon sheath results in decreased lubrication leading to tissue damage and dystrophic calcification. These pathological changes within tendon and tendon sheath in Prg4 −/− mice resulted in camptodactyly similar to that observed in human CACP patients.
Prg4 −/− mouse was generated. Aging Prg4 −/− mice show progressive joint failure. Prg4 −/− mouse is a model for human CACP; OMIM 208250.
Prg4 plays a role in interfascicular lubrication in tendon. The study involved pulling of a 15 mm long fascicle segment proximally from a distally cut tail of 10–16-week Prg4 −/−, Prg4 +/−, and Prg4 +/+ mice. The mean peak gliding resistance was more in homozygote mutant than Het and WT mice (43.2, 35.4, and 28.5 mN, resp.).
Prg4 expression plays a role in the viscoelastic properties of tail tendon fascicles. Tendon stiffness and viscoelasticity was determined in 10–13-week Prg4 −/−, Prg4 +/−, and Prg4 +/+ mice. A ramp test was used to determine the elastic modulus by pulling the fascicles to 2.5% strain amplitude at a rate of 0.05 mm/s followed by a relaxation test that pulled the fascicles to 5% strain amplitude at a rate of 2 mm/s. The fascicles were allowed to relax for 2 min at the maximum strain and a single-cycle relaxation ratio was used to characterize the viscoelastic properties. Prg4 homozygous mutant mice had lower relaxation ratio than the WT mice.
In two sisters with congenital camptodactyly and joint effusions, abnormalities in tendons were restricted to the portion within synovial sheaths implying a disease of the tenosynovium. In areas of chronic involvement, some tendons were replaced by fibrous tissue. Fingers, in the patient with the disease, had hard scarring tissue.
Mutations in CACP/PRG4 gene, causing disease, were identified as four deletion mutations (2805del5, 3240del7, 3023del2, and 3690del5) that alter the reading frame and result in premature truncation of the full-length polypeptide.
Sequence analysis of PRG4 gene, in the affected individuals of a Pakistani family with CACP syndrome, revealed a 2-base-pair deletion (c.2816_2817delAA) predicting a frame shift mutation (p.Lys939fsX38).
