A novel nonosteocytic regulatory mechanism of bone modeling

Abstract

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.

Cellular diversity of the regenerating caudal fin

“…Of the two preinjury subgroups, M-2 represented the mature bone lineage, which was enriched for expressions of bglap, mgp, and sost ( fig. S6E) (36,37). Comparing to M-2, cluster M-1 presented low expression levels of bglap, mgp, and sost and high expression levels of a group of other genes, including fhl1a, fhl2a, and tagln ( fig.…”

Potential of zebrafish as a model to characterise MicroRNA profiles in mechanically mediated joint degeneration

“…The presence of lower jaw cartilages in which loading can be manipulated allows miRs which are responsive to mechanical load to be isolated (Chen et al 2005 ) and identified so that specific pathways can be dysregulated through CRISPR/cas9-induced mutation of miR signalling pathway components or through immersion in miR agonists/antagonists and the effect on chondrocytes studied. Other skeletal elements in zebrafish, such as the vertebral centra, have also been demonstrated to be mechanically sensitive, and to undergo remodelling in response to load (Fiaz et al 2012 ; Ofer et al 2019 ), which could be regulated by miRs. Finite element models also exist for the zebrafish vertebral column (Newham et al 2019 ; Ofer et al 2019 ).…”

Abnormal craniofacial and spinal bone development withcol2a1a depletion in a zebrafish model of CHARGE syndrome

“…(26) Yet, a recent zebrafish model has proven valuable in the modelling of chd7 dependent CS revealing a reduction in vertebrae mineralization of young larvae. (27) Zebrafish have become increasingly relevant in the study of fundamental bone development and bone related disorders (28)(29)(30) , including scoliosis, osteoporosis, age related osteoarthritis. (31,32) Notably, the spinal structure in zebrafish has been characterized in detail and comprises three major regions: the Weberian apparatus, a specialized structure consisting of the first four vertebrae connecting the auditory system and the swim bladder to amplify sound vibrations, the precaudal vertebrae which are connected to neural arch and spines to form the chest and, the caudal vertebrae of the tail region with neural and hemal arch.…”

“…(33) Simplicity of analysis in zebrafish to investigate spinal structures has been used to understand the effects of mechanical loading on bone mineralization. (30,34) Zebrafish have specific advantages in the analysis of skeletal development such as the closely related structure to humans, rapid bone development with first mineralization of vertebrate occurring after only 5 days post fertilization (dpf), as well as ex utero development and transparency of young larvae simplifying the use of in vivo staining and transgenic lines to allow for the analysis of early calcification in zebrafish bony structures. (35)(36)(37)(38) Furthermore, the simplicity of high-throughput drug screening in this teleost model makes the model highly useful for investigating new drug targets and effect on skeletal development.…”