Quantifying the tolerance of chick hip joint development to temporary paralysis and the potential for recovery

Abstract

Background: Abnormal fetal movements are implicated in joint pathologies such as arthrogryposis and developmental dysplasia of the hip (DDH). Experimentally induced paralysis disrupts joint cavitation and morphogenesis leading to postnatal abnormalities. However, the developmental window(s) most sensitive to immobility-and therefore the best time for intervention-have never been identified. Here, we systematically vary the timing and duration of paralysis during early chick hip joint development. We then test whether external manipulation of immobilized limbs can mitigate the effects of immobility. Results: Timing of paralysis affected the level of disruption to joints, with paralysis periods between embryonic days 4 and 7 most detrimental. Longer paralysis periods produced greater disruption in terms of failed cavitation and abnormal femoral and acetabular geometry. External manipulation of an immobilized limb led to more normal morphogenesis and cavitation compared to un-manipulated limbs. Conclusions: Temporary paralysis is detrimental to joint development, particularly during days 4 to 7. Developmental processes in the very early stages of joint development may be critical to DDH, arthrogryposis, and other joint pathologies. The developing limb has the potential to recover from periods of immobility, and external manipulation provides an innovative avenue for prevention and treatment of developmental joint pathologies.

Joint development recovery on resumption of embryonic movement following paralysis

“…The achievement of recovery is also supported by the demonstration of the effects of the short-term period of immobilisation alone (E4-E6) which causes similar defects to sustained immobilisation with reduction of the knee and hip joint interzone (Fig 1). This same early period of immobilisation is also reported to have most severe effects on hip development (Bridglal et al, 2020). (which was not certified by peer review) is the author/funder.…”

“…Having established that embryonic motility partially resumes following short term immobilisation, we examined joint development, comparing the effects of both recovery scenarios to sustained absence of movement, and control specimens. Joint development is an important focus to assess the potential for recovery for two reasons: 1) the clinical relevance of joint developmental defects due to reduced fetal movement during pregnancy and 2) extensive characterisation of the effects of immobilisation on joint development in animal models, particularly the knee and hip joints in the chick (Bridglal et al, 2020;Sotiriou et al, 2019;Brunt et al, 2016;Nowlan et al, 2014;Roddy et al, 2011b;Nowlan et al, 2010a;Osborne et al, 2002). It was previously noted that chick elbow joints were affected similarly to knee joints (Roddy et al, 2011b) but here we describe elbow joint effects for the first time.…”

“…The effects of immobilisation by rigid paralysis using the neuromuscular blocking agent DMB on skeletal development have been previously documented across various treatment periods including detailed analysis of the effects on knee joint development with treatment between E4.5 and E7 (Roddy et al, 2011b), on hip development over a series of treatment times and durations with early immobilisation from E4 for 3 days being most disruptive (Bridglal et al, 2020;Nowlan et al, 2014) and effects on spinal development with treatments from E3 to E9 (Levillain et al, 2019;Rolfe et al, 2017). Here we examine the capacity for recovery from effects at multiple joints and the spine following early immobilisation between E4 and E6 analysed at E10.…”

“…Joint shape abnormalities in infants are shown to be somewhat plastic, for example if congenital developmental dysplasia of the hip is identified early, joint shape can be 'reset; by harnesses (reviewed in Vaquero-Picado et al, 2019). A recent study used physical external manipulation of hip joints in immobilised chick embryos, and showed more normal joint morphogenesis compared to unmanipulated contralateral limbs (Bridglal et al, 2020). This important question has implications for the long-term potential for recovery in conditions caused by fetal immobilisation and the potential development of therapies, either in utero or post-natal, to ameliorate the effects of restricted movement.…”

Musculoskeletal development, maintenance and regeneration: Part two

“…Environmental factors also influence skeletal development and are common causes of abnormalities such as developmental dysplasia of the hip and club foot. Using the chick embryo and the developing hip joint as model systems, Bridglal et al 5 now pinpoint a critical developmental window in which movement is essential. The authors show that transient paralysis of embryonic movements during the early stages of joint formation prior to joint cavitation result in the most severe defects in joint shape and cavitation.…”