GDF-5 deficiency in mice alters the ultrastructure, mechanical properties and composition of the Achilles tendon.
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.
Mikic
B
B
Department of Orthopaedic Surgery, University of Virginia, Charlottesville 22908, USA. bmikic@email.smith.edu
Schalet
B J
BJ
Clark
R T
RT
Gaschen
V
V
Hunziker
E B
EB
D000125:Achilles Tendon / Q000737:chemistry / Q000502:physiology / Q000648:ultrastructure; D000818:Animals; D019485:Bone Morphogenetic Proteins; D003094:Collagen / Q000648:ultrastructure; D004247:DNA / Q000032:analysis; D006025:Glycosaminoglycans / Q000032:analysis; D055428:Growth Differentiation Factor 5; D006133:Growth Substances / Q000172:deficiency* / Q000235:genetics*; D006579:Heterozygote; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008854:Microscopy, Electron; D013314:Stress, Mechanical
D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D006025:Glycosaminoglycans; D055428:Growth Differentiation Factor 5; D006133:Growth Substances; D003094:Collagen; D004247:DNA; D006909:Hydroxyproline