Joint development recovery on resumption of embryonic movement following paralysis

Abstract

Fetal activity in utero is a normal part of pregnancy and reduced or absent movement can lead to long-term skeletal defects such as Fetal Akinesia Deformation Sequence (FADS), joint dysplasia and arthrogryposis. A variety of animal models with decreased or absent embryonic movements show a consistent set of developmental defects providing insight into the aetiology of congenital skeletal abnormalities. At developing joints defects include reduced joint interzones with frequent fusion of cartilaginous skeletal rudiments across the joint. At the spine defects include shortening and a spectrum of curvature deformations. An important question, with relevance to possible therapeutic interventions for human conditions, is the capacity for recovery with resumption of movement following short term immobilisation. Here we use the well-established chick model to compare the effects of sustained immobilisation from embryonic day (E) 4-10 to two different recovery scenarios: (i) natural recovery from E6 until E10 and (ii) the addition of hyperactive movement stimulation during the recovery period. We demonstrate partial recovery of movement and partial recovery of joint development under both recovery conditions, but no improvement in spine defects. The joints examined (elbow, hip and knee) showed better recovery in hindlimb than forelimb, with hyperactive mobility leading to greater recovery in the knee and hip. The hip joint showed the best recovery with improved rudiment separation, tissue organisation and commencement of cavitation. This work demonstrates that movement post paralysis can partially-recover specific aspects of joint development which could inform therapeutic approaches to ameliorate the effects of human fetal immobility.

Restraint upon Embryonic Metatarsal Ex Vivo Growth by Hydrogel Reveals Interaction between Quasi-Static Load and the mTOR Pathway

“…Our data reveal a very dramatic mechanically-engendered inhibition of longitudinal growth in hydrogel, suggesting that prolonged static compressive loads may evoke an irreversible blockade of EO. Studies in chick embryos have shown that the effects of 'rigid' paralysis at early embryo stages, which would likewise engender quasi-static load, could be partially overcome in the spine, but not in developing joints, by restoring movement [16]. This suggests that the dynamic loads associated with movement may reverse some of the effects of quasi-static loading.…”

“…Specific connections between endochondral growth and local mechanical stimuli are emerging. Mechanical stimuli have, for example, been shown to regulate cartilage growth [9][10][11], and animal models in which movement is restricted show impaired growth [12][13][14][15][16]. Despite these connections, the candidate regulators through which mechanical factors interact to control endochondral growth are ill-defined.…”

Cyclical compression loading is the dominant mechanoregulator of synovial joint morphogenesis

“…Insights on cartilage mechanoregulation can be gained by studying the effects of mechanical loads on cartilage in vivo/in ovo, cartilage explants ex vivo or chondrocytes in vitro. In vivo [5], in ovo [4,9] and in vitro [20] studies have shown that the development of functioning joints depends on the timing and duration of movement. While early movements, prior to joint cavitation (the physical separation .…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 10, 2023. ; https://doi.org/10.1101/2023.02.09.527957 doi: bioRxiv preprint of the skeletal elements), are crucial for the separation of joint elements [4,5,7,9,12,15], short periods of immobility after cavitation has taken place have only minor influence on joint morphology [4]. However, long periods of immobilisation, even after cavitation has occurred, result in marked shape changes which can lead to joint fusion in most extreme cases in chick limbs [4,9,12] and larval zebrafish jaws [5,7,15]. Fetal chick knees cultured in vitro showed that the duration of loading is an important factor influencing joint growth and morphogenesis, with longer durations resulting in more normally developed joints [20].…”

“…Insights on cartilage mechanoregulation can be gained by studying the effects of mechanical loads on cartilage in vivo/in ovo , cartilage explants ex vivo or chondrocytes in vitro. In vivo [5], in ovo [4, 9] and in vitro [20] studies have shown that the development of functioning joints depends on the timing and duration of movement. While early movements, prior to joint cavitation (the physical separation of the skeletal elements), are crucial for the separation of joint elements [4, 5, 7, 9, 12, 15], short periods of immobility after cavitation has taken place have only minor influence on joint morphology [4].…”