Biology subjects

Leek, C. C.

Publications and source records attributed to Leek, C. C..

3 recordsLinked to original sources

bioRxiv2021

Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death

Tendons and ligaments are structural tissues that attach to bone and are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (i.e., entheses) are often found at bony protrusions (i.e., eminences), and the shape and size of these protrusions depends on both mechanical forces and cellular cues during growth and development. The formation of tendon eminences also contributes to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where tendon and ligament attachments can be found. However, the role of FGFR signaling in attachment development and maintenance in the limb remains unknown. In this study, we used transgenic mouse models for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/ligament and attachment progenitors using ScxCre and measured eminence size and bone shape in the appendicular skeleton. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal appendicular skeleton and smaller secondary ossification centers in long bones. In addition, Fgfr1 Fgfr2 double conditional knockout mice had more variation in the size of collagen fibrils in tendon, narrowed synovial joint spacing, and increased cell death at sites of ligament attachments, as well as decreased plasticity of mature bone compared to age-matched wildtype littermates. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences.

physiology↗

bioRxiv2021

Deletion of Fibroblast growth factor 9 globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments

The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon-bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion of fibroblast growth factor 9 (Fgf9), the DT size is notably enlarged. In this study, we explored the tissue-specific regulation of DT size using both global and targeted deletion of Fgf9. We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss of Fgf9. Loss of Fgf9 during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development in Fgf9null attachments. We then showed that targeted deletion of Fgf9 in skeletal muscle leads to postnatal enlargement of the DT. Taken together, we discovered that Fgf9 may play an influential role in muscle-bone crosstalk during embryonic and postnatal development.

developmental biology↗

bioRxiv2020

Mechanics and Differential Healing Outcomes of Small and Large Partial-Thickness Injuries of the Rat Rotator Cuff

The size of rotator cuff tears affects clinical outcomes following rotator cuff repair and is correlated with risk of re-injury. This study aimed to understand how defect size influences the structural and mechanical outcomes of the injured rotator cuff attachment in vivo. We used our previously established model of full-thickness injury of the rotator cuff tendon-bone attachment in Long Evans rats to compare differences in healing outcomes between small and large defects. Biomechanical properties, gross morphology, bone remodeling, and cell and tissue morphology were assessed at 3- or 8-weeks of healing. At the time of injury (no healing), large defects had decreased mechanical properties compared to small defects, and both defect sizes had decreased mechanical properties compared to intact attachments. The mechanical properties of the defect groups were comparable after 8-weeks of healing and significantly improved compared to no healing but failed to return to intact levels. Local bone volume at the defect site was higher in large compared to small defects on average and increased from 3- to 8-weeks. Contrastingly, bone quality, measured as bone volume percentage and trabecular morphometry, of the total epiphysis and greater tubercle decreased from 3- to 8-weeks of healing and these changes were not dependent on defect size. Qualitatively, we observed that large defects had increased disorganized collagen and neovascularization compared to small defects. In this study, we demonstrated that not only small but also large defects do not regenerate the mechanical and structural integrity of the intact rat rotator cuff attachment following healing in vivo. Statement of Clinical SignificanceOur rat model of full-thickness rotator cuff tears may be beneficial to understand and prevent tear enlargement in vivo.

bioengineering↗