The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones

Blecher, Ronen; Krief, Sharon; Galili, Tal; Assaraf, Eran; Stern, Tomer; Anekstein, Yoram; Agar, Gabriel; Zelzer, Elazar

doi:10.1016/j.celrep.2017.07.073

Cited by 24 publications

(25 citation statements)

References 71 publications

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“…By evincing a shared bone-building response mechanism in osteocytic and anosteocytic bone types, our observations provide experimental validation for recent speculations that vertebrate skeletal mechanobiology is less osteocyte-centric than currently believed [11,12,32]. Sporadic reports have noted SOST expression by several nonosteocytic cells in mammals—by hypertrophic and osteoarthritic chondrocytes [33,34], osteoblast-like osteosarcoma cells [35,36], and even in normal osteoblasts, albeit at low levels [25,37]; however, these observations were not linked to bone-modeling regulation.…”

Section: Discussionsupporting

confidence: 73%

A novel nonosteocytic regulatory mechanism of bone modeling

et al. 2019

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Osteocytes, cells forming an elaborate network within the bones of most vertebrate taxa, are thought to be the master regulators of bone modeling, a process of coordinated, local bone-tissue deposition and removal that keeps bone strains at safe levels throughout life. Neoteleost fish, however, lack osteocytes and yet are known to be capable of bone modeling, although no osteocyte-independent modeling regulatory mechanism has so far been described. Here, we characterize a novel, to our knowledge, bone-modeling regulatory mechanism in a fish species (medaka), showing that although lacking osteocytes (i.e., internal mechanosensors), when loaded, medaka bones model in mechanically directed ways, successfully reducing high tissue strains. We establish that as in mammals, modeling in medaka is regulated by the SOST gene, demonstrating a mechanistic link between skeletal loading, SOST down-regulation, and intense bone deposition. However, whereas mammalian SOST is expressed almost exclusively by osteocytes, in both medaka and zebrafish (a species with osteocytic bones), SOST is expressed by a variety of nonosteocytic cells, none of which reside within the bone bulk. These findings argue that in fishes (and perhaps other vertebrates), nonosteocytic skeletal cells are both sensors and responders, shouldering duties believed exclusive to osteocytes. This previously unrecognized, SOST -dependent, osteocyte-independent mechanism challenges current paradigms of osteocyte exclusivity in bone-modeling regulation, suggesting the existence of multivariate feedback networks in bone modeling—perhaps also in mammalian bones—and thus arguing for the possibility of untapped potential for cell targets in bone therapeutics.

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Section: Discussionsupporting

confidence: 73%

A novel nonosteocytic regulatory mechanism of bone modeling

et al. 2019

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“…The regulatory role of the proprioceptive system can be either non-autonomous or mediated by autonomous mechanisms. Our two recent reports [28,95] provide examples for non-autonomous regulation, where the proprioceptive system serves as the sensor that activates muscles to achieve skeletal integrity and alignment. Given that the skeleton is a mechanosensitive tissue, it is tempting to speculate that the proprioceptive system can also influence the autonomous response of the skeleton to a changing mechanical environment.…”

Section: The Regulatory Role Of the Proprioceptive System In Musculosmentioning

confidence: 99%

New functions for the proprioceptive system in skeletal biology

Blecher

Heinemann-Yerushalmi

Assaraf

et al. 2018

Phil. Trans. R. Soc. B

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Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones. These discoveries have been made in several mouse lines lacking functional mechanosensors in part or completely. In both studies, the absence of functional spindles and GTOs produced a more severe phenotype than that of spindles alone. Interestingly, the spinal curve phenotype, which appeared during peripubertal development, bears resemblance to the human condition adolescent idiopathic scoliosis. This similarity may contribute to the study of the disease by offering both an animal model and a clue as to its aetiology. Moreover, it raises the possibility that impaired proprioceptive signalling may be involved in the aetiology of other conditions. Overall, these new findings expand considerably the scope of involvement of proprioception in musculoskeletal development and function. This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

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“…The intact morphology of the spine and hip joint in mutants lacking Piezo2 in skeletal cells prompted us to search for the tissue in which Piezo2 activity could affect the skeleton nonautonomously. Recently, we have demonstrated the regulatory role of the proprioceptive system in skeletal integrity 38,39 . Since Piezo2 is expressed and functions in proprioceptive neurons 14,40 , we speculated that loss of Piezo2 in these neurons could lead to skeletal abnormalities.…”

Section: Resultsmentioning

confidence: 99%

Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity

et al. 2020

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In humans, mutations in the PIEZO2 gene, which encodes for a mechanosensitive ion channel, were found to result in skeletal abnormalities including scoliosis and hip dysplasia. Here, we show in mice that loss of Piezo2 expression in the proprioceptive system recapitulates several human skeletal abnormalities. While loss of Piezo2 in chondrogenic or osteogenic lineages does not lead to human-like skeletal abnormalities, its loss in proprioceptive neurons leads to spine malalignment and hip dysplasia. To validate the non-autonomous role of proprioception in hip joint morphogenesis, we studied this process in mice mutant for proprioceptive system regulators Runx3 or Egr3. Loss of Runx3 in the peripheral nervous system, but not in skeletal lineages, leads to similar joint abnormalities, as does Egr3 loss of function. These findings expand the range of known regulatory roles of the proprioception system on the skeleton and provide a central component of the underlying molecular mechanism, namely Piezo2.

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The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones

Cited by 24 publications

References 71 publications

A novel nonosteocytic regulatory mechanism of bone modeling

A novel nonosteocytic regulatory mechanism of bone modeling

New functions for the proprioceptive system in skeletal biology

Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity

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