How the “Sixth Sense” Shapes the Skeleton

03.09.2020

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The findings point to a surprising origin for scoliosis and hip dysplasia

A distorted skeleton interferes with movement, but more surprisingly, the reverse is also true: Distortions in the way we move can cause problems with skeletal development in the first place. A new study by researchers at the Weizmann Institute of Science reveals that mutations in the sensory system known as proprioception – which enables us to sense our bodies at rest and during movement – can lead to such skeletal abnormalities as scoliosis and hip dysplasia.

Prof. Elazar Zelzer of the Molecular Genetics Department discovered in earlier research that proprioception – sometimes referred to as the “sixth sense,” the ability to naturally perceive the position of our body parts – plays a role in bone healing and keeps the maturing skeleton healthy and well-aligned. He showed, in particular, that developing bones crucially depend on the proper functioning of muscle spindles: structures consisting of nerve endings coiled around muscle fibers, which convey information about muscle extension and contraction to the proprioceptive system.

Now orthopedic surgeon Dr. Eran Assaraf from Shamir Medical Center (Assaf Harofeh), who is working on a PhD in Zelzer’s lab, has uncovered a molecular mechanism that plays a key role in the transfer of mechanical signals from muscles to proprioceptive neurons. Assaraf and colleagues focused on a gene called Piezo2 that regulates the passage of positive ions through cellular membranes and is known to be mechanosensitive, that is, responsive to mechanical stimulation. Defects in this gene have been implicated in skeletal abnormalities in human beings, but because Piezo2 is expressed in a wide variety of cells and tissues, it was unclear how these abnormalities come about.

It might be possible to alleviate skeletal abnormalities by the right kind of movement

To find out, the researchers created several types of transgenic mice, in each of which Piezo2 was silenced in a different kind of cell. When the gene was silenced in bone cells called osteoblasts and chondrocytes, no skeletal deformities were seen in these mice as they grew up. In contrast, when the scientists silenced Piezo2 in proprioceptive neurons in the muscle spindles and elsewhere, the mutant mice ended up with scoliosis and hip dysplasia. These skeletal deformities, revealed by micro-CT scans, were similar to those observed in humans with mutations in the human equivalent of the Piezo2 gene.

These findings support the notion that the proprioceptive system regulates the skeleton and, for the first time, they reveal a molecular mechanism by which such regulation takes place. In more practical terms, the study opens up a possible new way of looking at skeletal abnormalities.

Since the proprioceptive system is essential to skeletal health – and since this system “informs” us about changes in muscle length, which, in turn, are caused by movement, it might be possible to alleviate skeletal abnormalities by the right kind of movement. In other words, it might be advisable to incorporate movement therapy into the treatment of such deformities as scoliosis and hip dysplasia, which are currently treated by movement restriction.

Study participants included orthopedic surgeon Dr. Ronen Blecher of Assuta Ashdod Medical Center; Lia Heinemann-Yerushalmi, Sharon Krief and Ron Carmel Vinestock of  the Zelzer lab; Dr. Inbal E. Biton of Weizmann’s Veterinary Resources Department; Dr. Vlad Brumfeld of Weizmann’s Chemical Research Support Department; Dr. Ron Rotkopf of Weizmann’s Life Sciences Core Facilities Department; and Drs. Erez Avisar and Gabriel Agar of Shamir Medical Center (Assaf Harofeh).

Prof. Elazar Zelzer is Head of the David and Fela Shapell Family Center for Genetic Disorders Research; his research is also supported by the Dr. Erhard, Emmi, and Fred Loewinsohn Center for Pediatric Health; the estate of Mr and Mrs van Adelsbergen; the Julie and Eric Borman Family Research Fund; the estate of Bernard Bishin for the WIS-Clalit Program; and the European Research Council. 

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