GDF‐5 deficiency in mice alters the ultrastructure, mechanical properties and composition of the Achilles tendon

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Abstract
Acromesomelic dysplasia of the Hunter-Thompson and Grebe types are rare human disorders based on growth/differentiation factor (GDF)-5/CDMP-1 genetic mutations. Numerous skeletal abnormalities are present in these individuals, including shortened limb bones and severe dislocations of the knee. In the GDF-5 deficient brachypodism mouse, similar, although less severe, phenotypes are observed. It is unknown whether the joint dislocations observed in these disorders are due to a defect in the original formation of joints such as the knee, or to abnormalities in the tendons and ligaments themselves. We hypothesized that tendons from GDF-5 deficient mice would exhibit altered composition, mechanical properties, and ultrastructure when compared with heterozygous control littermates. GDF-5 deficient Achilles tendons were structurally weaker than controls, and structural strength differences appeared to be caused by compromised material properties: after normalizing by collagen per unit length, mutant tendons were still 50% weaker (P < 0.0001) and 50% more compliant (P < 0.001) than controls. Despite comparable levels of skeletal maturity in the two cohorts, the majority of mutant tendon failures occurred in the mid-substance of the tendon (64% of all failures), whereas the majority of control failures occurred via avulsion (92% of all failures). Mutant Achilles tendons contained 40% less collagen per microgram of DNA when compared to controls (P = 0.004). No significant difference in glycosaminoglycan (GAG)/DNA was detected. Ultrastructural analyses indicated a slight trend toward increased frequency of small diameter (30-100 nm) collagen fibrils in the mutant Achilles. Our findings suggest that increased tendon and ligament laxity may be the cause of the joint dislocations seen in patients with Hunter-Thompson and Grebe type dysplasia, rather than developmental abnormalities in the joints themselves.