More Like this

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

   https://doi.org/10.1002/dvdy.600  

   Wernlé, Kendra_K ; Sonnenfelt, Michael_A ; Leek, Connor_C ; Ganji, Elahe ; Sullivan, Anna_Lia ; Offutt, Claudia ; Shuff, Jordan ; Ornitz, David_M ; Killian, Megan_L ( May 2023 , Developmental Dynamics)

   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, andFgfr1andFgfr2are highly expressed in the perichondrium and periosteum of bone where entheses can be found.

   We used transgenic mice for combinatorial knockout ofFgfr1and/orFgfr2in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual,Fgfr1andFgfr2inScxprogenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition,Fgfr1/Fgfr2double 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.

    

   more » « less
2. Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice

   https://doi.org/10.1126/sciadv.adf4683  

   Ganji, Elahe ; Lamia, Syeda N ; Stepanovich, Matthew ; Whyte, Noelle ; Goulet, Robert W ; Abraham, Adam C ; Killian, Megan L ( June 2023 , Science Advances)

   Skeletal shape depends on the transmission of contractile muscle forces from tendon to bone across the enthesis. Loss of muscle loading impairs enthesis development, yet little is known if and how the postnatal enthesis adapts to increased loading. Here, we studied adaptations in enthesis structure and function in response to increased loading, using optogenetically induced muscle contraction in young (i.e., growth) and adult (i.e., mature) mice. Daily bouts of unilateral optogenetic loading in young mice led to radial calcaneal expansion and warping. This also led to a weaker enthesis with increased collagen damage in young tendon and enthisis, with little change in adult mice. We then used RNA sequencing to identify the pathways associated with increased mechanical loading during growth. In tendon, we found enrichment of glycolysis, focal adhesion, and cell-matrix interactions. In bone, we found enrichment of inflammation and cell cycle. Together, we demonstrate the utility of optogenetic-induced muscle contraction to elicit in vivo adaptation of the enthesis.

    

   more » « less
3. Zebrafish endochondral growth zones as they relate to human bone size, shape and disease

   https://doi.org/10.3389/fendo.2022.1060187  

   Le Pabic, Pierre ; Dranow, Daniel B. ; Hoyle, Diego J. ; Schilling, Thomas F. ( December 2022 , Frontiers in Endocrinology)

   Research on the genetic mechanisms underlying human skeletal development and disease have largely relied on studies in mice. However, recently the zebrafish has emerged as a popular model for skeletal research. Despite anatomical differences such as a lack of long bones in their limbs and no hematopoietic bone marrow, both the cell types in cartilage and bone as well as the genetic pathways that regulate their development are remarkably conserved between teleost fish and humans. Here we review recent studies that highlight this conservation, focusing specifically on the cartilaginous growth zones (GZs) of endochondral bones. GZs can be unidirectional such as the growth plates (GPs) of long bones in tetrapod limbs or bidirectional, such as in the synchondroses of the mammalian skull base. In addition to endochondral growth, GZs play key roles in cartilage maturation and replacement by bone. Recent studies in zebrafish suggest key roles for cartilage polarity in GZ function, surprisingly early establishment of signaling systems that regulate cartilage during embryonic development, and important roles for cartilage proliferation rather than hypertrophy in bone size. Despite anatomical differences, there are now many zebrafish models for human skeletal disorders including mutations in genes that cause defects in cartilage associated with endochondral GZs. These point to conserved developmental mechanisms, some of which operate both in cranial GZs and limb GPs, as well as others that act earlier or in parallel to known GP regulators. Experimental advantages of zebrafish for genetic screens, high resolution live imaging and drug screens, set the stage for many novel insights into causes and potential therapies for human endochondral bone diseases. 

   more » « less
4. Getting into Shape: Limb Bone Strength in Perinatal Lemur catta and Propithecus coquereli

   https://doi.org/10.1002/ar.24045  

   Young, Jesse_W ; Jankord, Kathryn ; Saunders, Marnie_M ; Smith, Timothy_D ( December 2018 , The Anatomical Record)

   Functional studies of skeletal anatomy are predicated on the fundamental assumption that form will follow function. For instance, previous studies have shown that the femora of specialized leaping primates are more robust than those of more generalized primate quadrupeds. Are such differences solely a plastic response to differential loading patterns during postnatal life, or might they also reflect more canalized developmental mechanisms present at birth? Here, we show that perinatalLemur catta, an arboreal/terrestrial quadruped, have less robust femora than perinatalPropithecus coquereli, a closely related species specialized for vertical clinging and leaping (a highly unusual locomotor mode in which the hindlimbs are used to launch the animal between vertical tree trunks). These results suggest that functional differences in long bone cross‐sectional dimensions are manifest at birth, belying simple interpretations of adult postcranial form as a direct record of loading patterns during postnatal life. Despite these significant differences in bone robusticity, we find that hindlimb bone mineralization, material properties, and measures of whole‐bone strength generally overlap in perinatalL. cattaandP. coquereli, indicating little differentiation in postcranial maturity at birth despite known differences in the pace of craniodental development between the species. In a broader perspective, our results likely reflect evolution acting during prenatal ontogeny. Even though primates are notable for relatively prolonged gestation and postnatal parental care, neonates are not buffered from selection, perhaps especially in the unpredictable and volatile environment of Madagascar. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 303:250–264, 2020. © 2018 American Association for Anatomy

    

   more » « less
5. Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle

   https://doi.org/10.1113/EP089301  

   West, Daniel W. D. ; Doering, Thomas M. ; Thompson, Jamie‐Lee M. ; Budiono, Boris P. ; Lessard, Sarah J. ; Koch, Lauren G. ; Britton, Steven L. ; Steck, Roland ; Byrne, Nuala M. ; Brown, Matthew A. ; et al ( February 2021 , Experimental Physiology)

   What is the central question of this study?

   The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload?

   What is the main finding and its importance?

   Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus.

   Divergent skeletal muscle phenotypes result from chronic resistance‐type versus endurance‐type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT;n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non‐overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. −6 ± 18%, mean ± SD,P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between‐group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload.In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

    

   more » « less