Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered

Moustafa, Alaa; Sugiyama, Toshihiro; Prasad, Jitendra; Zaman, Gul; Gross, TS; Lanyon, Lance E.; Price, J. S.

doi:10.1007/s00198-011-1656-4

Cited by 214 publications

(218 citation statements)

References 45 publications

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“…Studies of both ulnar and tibial loading in mice have been shown to decrease levels of the sclerostin protein expression, whereas unloading has been shown to increase levels of sclerostin [63]. These changes are highly correlated with sites of anabolic bone formation in the loading models [63][64][65][66]. Taken all together, these studies highlight the essential role of osteocytes in both immediate mechanosensation and the coordination of later adaptive responses.…”

Section: Tissue-level Adaptationmentioning

confidence: 86%

Experimental studies of bone mechanoadaptation: bridging in vitro and in vivo studies with multiscale systems

Brown¹,

Sattler²

2016

Interface Focus.

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Despite advancements in technology and science over the last century, the mechanisms underlying Wolff's law—bone structure adaptation in response to physical stimuli—remain poorly understood, limiting the ability to effectively treat and prevent skeletal diseases. A challenge to overcome in the study of the underlying mechanisms of this principle is the multiscale nature of mechanoadaptation. While there exist in silico systems that are capable of studying across these scales, experimental studies are typically limited to interpretation at a single dimension or time point. For instance, studies of single-cell responses to defined physical stimuli offer only a limited prediction of the whole bone response, while overlapping pathways or compensatory mechanisms complicate the ability to isolate critical targets in a whole animal model. Thus, there exists a need to develop experimental systems capable of bridging traditional experimental approaches and informing existing multiscale theoretical models. The purpose of this article is to review the process of mechanoadaptation and inherent challenges in studying its underlying mechanisms, discuss the limitations of traditional experimental systems in capturing the many facets of this process and highlight three multiscale experimental systems which bridge traditional approaches and cover relatively understudied time and length scales in bone adaptation.

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Section: Tissue-level Adaptationmentioning

confidence: 86%

Experimental studies of bone mechanoadaptation: bridging in vitro and in vivo studies with multiscale systems

Brown¹,

Sattler²

2016

Interface Focus.

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“…cell signaling | electrophysiology | mechanotransduction | junctional conductance I ncreasing evidence indicates that bone homeostasis and osteogenic remodeling require mechanical loading of whole bone tissue (1)(2)(3)(4). Interstitial fluid in bone passes through hierarchical levels of porosity when bone tissue is deformed by external loads.…”

mentioning

confidence: 99%

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Schaffler

Weinbaum

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid-flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotidedegrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network.cell signaling | electrophysiology | mechanotransduction | junctional conductance I ncreasing evidence indicates that bone homeostasis and osteogenic remodeling require mechanical loading of whole bone tissue (1-4). Interstitial fluid in bone passes through hierarchical levels of porosity when bone tissue is deformed by external loads. The interstitial fluid is the medium that translates endogenous whole tissue mechanical loads to cellular level forces in bone. Measuring the magnitude of endogenous forces acting on osteocytes in vivo has been a major challenge experimentally, but is of significance for investigating force-induced cell signals in vitro. Mathematical models of in vivo forces acting within the bone porosity of the lacunar-canalicular system (LCS) containing osteocytes have theoretically predicted forces between 1 and 10 pN acting on attachment sites along the osteocyte cell process membrane (5-7). These predictions guided the development of a Stokesian fluid stimulus probe (SFSP) used to focally stimulate osteocytes in vitro at in vivo-level forces (8). In this study, we examined the intercellular electrical signals induced by pN-level forces in interconnected MLO-Y4 bone cell networks, and measured the intercellular signaling through gap junction channels and through changes in nonjunctional conductance. Signaling through nonjunctional membranes likely involves ATP release and binding to purinergic receptors (P2Rs), as demonstrated by the partia...

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“…For that reason, the addition of finite element analysis models has been crucial in enabling us to understand the strain field engendered on bone for the various animal loading modalities. Numerous studies have explored strain distributions under the loading regimes, each involving increasingly more sophisticated models [65][66][67][68][69][70][71][72]. Digital image correlation (DIC) has also been used to assess surface strains experimentally.…”

Section: Extrinsic Factors Influencing Bone Formation Responsementioning

confidence: 99%

Bone Quality and Quantity are Mediated by Mechanical Stimuli

Berman

Wallace

2016

Clinic Rev Bone Miner Metab

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Prevention of fracture through improved bone mechanical strength is of great importance given the large number of bone disease-related fractures each year, the decreased quality of life associated with fractures, and the large anticipated increase in fracture incidence over the upcoming years due to the aging population. Exercise and other forms of mechanical stimulation have been shown to increase bone mass, suggesting improved strength. However, while bone mass is a good indicator of strength, other components (such as bone quality) also contribute to bone mechanical integrity. While increased bone mass has been explored considerably using both exercise and targeted loading models, the role of mechanical stimulation in altering bone quality has been explored to a lesser degree. Understanding how to improve both the quantity and quality of bone is critical to increasing fracture resistance. Herein, we discuss quantity and quality-based improvements that have been observed using both exercise and targeted loading models of bone adaptation.

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Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered

Cited by 214 publications

References 45 publications

Experimental studies of bone mechanoadaptation: bridging in vitro and in vivo studies with multiscale systems

Experimental studies of bone mechanoadaptation: bridging in vitro and in vivo studies with multiscale systems

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Bone Quality and Quantity are Mediated by Mechanical Stimuli

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