Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 25, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2100690118
Keywords
osteogenesis imperfecta; Fkbp10; tendon; ligament; contracture
Categories
Funding
- NIH [P01 HD070394, F32AR070612, F31DE02248, AI036211, CA125123, RR024574]
- Baylor College of Medicine (BCM) Intellectual & Developmental Disabilities Research Center from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [HD024064]
- BCM Advanced Technology Cores
- Rolanette and Berdon Lawrence Bone Disease Program of Texas
- BCM Center for Skeletal Medicine and Biology
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This study reveals that defects in Fkbp10 in tendons and ligaments can cause joint dysfunction in osteogenesis imperfecta, involving ectopic chondrogenesis and dysregulated Hedgehog signaling.
Y Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 (FKBP10) lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. In this study, we have generated a mouse model in which Fkbp10 is conditionally deleted in tendons and ligaments. Fkbp10 removal substantially reduced telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons. These biochemical alterations resulting from Fkbp10 ablation were associated with a site-specific induction of fibrosis, inflammation, and ectopic chondrogenesis followed by joint deformities in postnatal mice. We found that the ectopic chondrogenesis coincided with enhanced Gli1 expression, indicating dysregulated Hedgehog (Hh) signaling. Importantly, genetic inhibition of the Hh pathway attenuated ectopic chondrogenesis and joint deformities in Fkbp10 mutants. Furthermore, Hh inhibition restored alterations in gait parameters caused by Fkbp10 loss. Taken together, we identified a previously unappreciated role of Fkbp10 in tendons and ligaments and pathogenic mechanisms driving OI joint dysfunction.
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