TGF-beta signaling has a well established role not only in adult organ homeostasis but also in skeletal development. Follistatin-like 3 (FSTL3), related to follistatin, is an inhibitor of TGF-beta ligands, with an established role in glucose and fat metabolism. However it has not previously been studied in skeletal development. Using a FSTL3 knock-out (KO) mouse model we have studied both embryonic skeletal development and adult bone phenotypes. Staining for skeletal and cartilage markers during development shows acceleration of skeletal tissue differentiation, with an eventual normalization at E18.5 (which is just prior to birth). Acceleration of bone mineralization occurs during both endochondral and intramembranous ossification. Use of micro-CT imaging highlighted the development of a scoliosis in the KO animals, along with abnormal shape of cranium and cranial sutures. Further investigation of the cranial phenotype in adult KO mice reveals craniosynastosis, with atypical fusion of the frontal suture. These mice have a change in overall cranial shape with shortening of the anterior head and a compensatory expansion of the posterior cranial bones, in a similar fashion to brachyencephaly. Our study therefore highlights a significant role of FSTL3 in skeletal tissue development and mineralization, as well as the development of clinically significant skeletal developmental disorders such as scoliosis, craniosynastosis and brachyencephaly.
Early diagnosis of delayed- and non-union tibial fractures is difficult, but treatment options are available if timely data are available. Direct correlation between implant forces and healing status is difficult during stance phase loading due to soft tissue forces. This ongoing study seeks to find a minimal set of strain gauge sites needed to determine healing at any of several fracture sites, using isometric loading suitable for routine clinical usage. A series of instrumented tibial nails are being used to help determine whether an alternative technology can replace or augment existing routine methods for assessment of fracture healing. In a prior study, a single strain gauge positioned close to the fracture site had produced mixed results. In the current study, a TRIGEN META NAIL, 10mm OD x 380mm long, was instrumented with 8 gauged sites spiraled down the nail at 34mm axial and 120deg angular separation (Gen1), and loaded in a Sawbone model in offset axial compression, 3 point bending and torque. In order to gain early clinical results, and in a design informed by the Gen1 data, a set of instrumented nails have been made for an ovine wireless telemetry study (Gen3a), shortly to commence, in which the tibial nail has been over-gauged enabling multiple d.o.f. measurements to be made during gait, torque, axial compression and 3 point bending; the latter protocols offering more controlled patient postures. This study is to be followed by a similar human study (Gen3) involving five subjects (12 gauges per nail). Meanwhile, a parallel biomechanical study involving six nails with 20 gauges each is also planned. In the Gen1 study, the strains diminished with distance from the fracture site and with out-of-plane sites during bending. During torque, however, the response was much more uniform for all strain sites. Significant increases in strains due to both loading regimes were seen in the fractured case vs. an intact bone. Preliminary conclusions are that strains measured due to applied torque may offer a more sensitive and fracture site-independent means of assessing healing than induced bending. We now aim to confirm these observations in animal and human studies.
