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

BACKGROUND: Tendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute 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 entheses can be found. RESULTS AND CONCLUSIONS: We used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. 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.

Mechanics and differential healing outcomes of small and large defect injuries of the tendon-bone attachment in the rat rotator cuff.

INTRODUCTION: Rotator cuff tear size affects clinical outcomes following rotator cuff repair and is correlated with the risk of recurrent tendon defects. This study aimed to understand if and how the initial defect size influences the structural and mechanical outcomes of the injured rotator cuff attachment in vivo. METHODS: Full-thickness punch injuries of the infraspinatus tendon-bone attachment in Long Evans rats were created 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 both 3- and 8-weeks of healing. RESULTS: 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. However, the mechanical properties of the two defect groups were not significantly different from each other 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. In contrast, bone quality decreased from 3- to 8-weeks of healing and these changes were not dependent on defect size. Qualitatively, large defects had increased collagen disorganization and neovascularization compared to small defects. DISCUSSION: In this study, we showed that both large and small defects did not regenerate the mechanical and structural integrity of the intact rat rotator cuff attachment following healing in vivo after 8 weeks of healing.

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

BACKGROUND: 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. RESULTS: 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. CONCLUSION: Taken together, we discovered that Fgf9 may play an influential role in muscle-bone cross-talk during embryonic and postnatal development.

Using tools in mechanobiology to repair tendons.

PURPOSE OF REVIEW: The purpose of this review is to describe the mechanobiological mechanisms of tendon repair as well as outline current and emerging tools in mechanobiology that might be useful for improving tendon healing and regeneration. Over 30 million musculoskeletal injuries are reported in the US per year and nearly 50% involve soft tissue injuries to tendons and ligaments. Yet current therapeutic strategies for treating tendon injuries are not always successful in regenerating and returning function of the healing tendon. RECENT FINDINGS: The use of rehabilitative strategies to control the motion and transmission of mechanical loads to repairing tendons following surgical reattachment is beneficial for some, but not all, tendon repairs. Scaffolds that are designed to recapitulate properties of developing tissues show potential to guide the mechanical and biological healing of tendon following rupture. The incorporation of biomaterials to control alignment and reintegration, as well as promote scar-less healing, are also promising. Improving our understanding of damage thresholds for resident cells and how these cells respond to bioelectrical cues may offer promising steps forward in the field of tendon regeneration. SUMMARY: The field of orthopaedics continues to advance and improve with the development of regenerative approaches for musculoskeletal injuries, especially for tendon, and deeper exploration in this area will lead to improved clinical outcomes.