Possible effect of fluid shear stress on osteoclastogenesis

Possible effect of fluid shear stress on osteoclastogenesis

आऋऑऎऊࣽईࣜऋंࣜ उँऀअࣿࣽईࣜ ࣿऋईईँःँएࣜऋंࣜऌईࣽ Journal of Medical Colleges of PLA 25 (2010) 103-109 www.elsevier.com/locate/jmcpla Possible effect of fluid s...

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आऋऑऎऊࣽईࣜऋंࣜ उँऀअࣿࣽईࣜ ࣿऋईईँःँएࣜऋंࣜऌईࣽ

Journal of Medical Colleges of PLA 25 (2010) 103-109


Possible effect of fluid shear stress on osteoclastogenesis Tong Xiaoyu, Xia Yayi* Orthopedic Department, Second Hospital, Lanzhou University, Lanzhou 730030, China Received 09 March 2010; accepted 17 April 2010

Abstract Bone remodeling is performed under the joint action of osteoblasts and osteoclasts. Since the effect of osteoclasts has been gradually recognized on bone and joint diseases, targeted researches toward osteoclasts have become a hot research field. This article reviews the relevant medical literature concerning the possible effects of the fluid shear stress (FSS) on the osteoclastogenesis chiefly from the aspects of RANKL-RANK-OPG system, the macrophage colony-stimulating factor (M-CSF), and calcitonin receptor (CTR). On the basis of the changes of the expression of osteoclastic activities, it is suggested that FSS is a potent, important regulator of bone metabolism. Keywords: Fluid shear stress (FSS); Osteoclastogenesis; RANKL; M-CSF

1. Introduction

bone tissues and cells under the fluid shear stress (FSS). The current studies suggest that FSS may lead to

Mechanical loading makes enormous impact on

positive bone formation. Since bone remodeling

bone metabolism. Actually, due to movement or body

depends on the effects of both osteoblasts and

position changes, a lot of bone tissues (especially cells)

osteoclasts, the influence of FSS on bone formation

are under dynamic liquid environment which generates

cannot be separated from the way how FSS affects

fluid flow. This fluid flow, driven by both vascular

these two cells. However, compared with osteoblasts,

pressure and mechanical loading, may generate

very little is known regarding osteoclasts because entry

significant shear stresses through the canaliculi as well

point for the study of them is very limited. Similarly,

as along the bone lining at the endosteal surface.

even less information is understood concerning the

Therefore, it is significant that exploring changes in



Corresponding authors.

Tel: 0931-8942580, E-mail address: [email protected](Xia Y.)






osteoclastogenesis. We are already familiar with a classical pathway


Tong Xiaoyu et al./Journal of Medical Colleges of PLA 25(2010) 103-109

for osteoclast-related study and it may be the most

and might have a role in the regulation of the











formation and activity [1]. This way contains RANK

researches indicate that the absence of RANK ligand

ligand, RANK receptor and its decoy receptor,

expression in mice results in severe osteopetrosis and

osteoprotegerin (OPG). What’s more, researches

absence of osteoclasts [7].

suggest that M-CSF may also play a critical role in

OPG, also called osteoclastogenesis inhibitory

osteoclastogenesis [2]. This factor is not only required

factor (OCIF), is a secreted member of the TNF

for early osteoclasts development, but may affect

receptor family. It inhibits osteoclastogenesis by acting

mature osteoclasts. In addition, calcitonin receptors

as a decoy receptor for ODF to compete against

(CTR), as a characteristic of osteoclasts, is a new focus

RANK [8].

whose research value has been paid increasing attention [3]. In view of the importance of the study on

2.2. The effect of FSS

osteoclasts, we commit to gathering the latest researches







osteoclastogenesis mainly from these aspects.

Kim and his colleagues [9] demonstrated that the decrease in RANKL/OPG was maximal immediately after the end of flow compared to no flow controls (P<

2. The RANKL-RANK-OPG system under FSS

0.05) and there existed a significant increase in OPG and decrease in RANKL with increasing load duration

2.1. RANKL-RANK-OPG system

of up to 2 h .They therefore concluded that FSS might play an important role in the regulation of bone osteoclast

remodeling. Moreover, they proposed it would be

differentiation factor (ODF), is a new member of the

possible that positive bone remodeling could be

TNF family and exists as a homotrimeric protein. It is

stimulated by exerting appropriate FSS to inhibit

expressed on the surface of osteoblastic cells and






proteolytically released as a soluble form. RANK,

Besides, Kim and his coworkers [10] also pointed

receptor activator of NF-țB, also called ODF and is

out that different frequency loading might lead to the

expressed on the surface of hemopoietic precursor cells

same performance of RANKL/OPG ratio. However, the

(osteoclast precursor cells) [4]. Current researches have

corresponding mechanisms were totally different.



Decreased RANKL/OPG ratio was due to an increase

osteoclastogenesis and we know that RANK directly

in OPG mRNA when under 3,600 cycles of OFF at 1

acts on precursor cells to stimulate their differentiation

Hz; whereas at 10 Hz the decrease was due to a decline

to mature osteoclasts[5]. Moreover, the latest research

in RANKL mRNA. Therefore, they concluded that

suggested that RANK–RANKL might be an important

applying different loading frequency might be a

regulator of interactions between T and dendritic cells

positive method to differentially control the change in





Tong Xiaoyu et al./Journal of Medical Colleges of PLA 25(2010) 103-109


the extracellular compartment. They also found that

either RANKL or OPG mRNA expression. Based on Kim and his team’s excellent work,

with the increase of FSS, levels of CAĊ mRNA

firstly we can make the following summary: it is

expression were proportional increased until it reached



a peak. On this basis, Zhang Q, et al concluded that

osteoclastogenesis through reducing RANKL/OPG.

with a certain range, FSS might increase osteolytic

Although they do not explain the detailed mechanism in

ability of osteoclast.





their first thesis, as a valuable academic point of view,

In view of these researches concerning FSS on

they have proposed that positive bone remodeling may

RANKL-RANK-OPG system, we can summarize them

be controlled by applying FSS. Meanwhile, their

as the following: Tan’s team demonstrates a possible

second research elaborates the mechanism by which

mechanism regarding how OFF influence OPG

positive bone formation can be achieved as target.

expression by the factor NO. This research gives us a

Researchers commit to establishing links between

better understanding of Kim and his coworkers’

frequency of FSS and RNA expression of RANKL or

scientific discovery. Nevertheless, as far as we are

OPG. Not only does this achievement make mechanism

concerned, the research by Zhang Q and his colleagues

concerning OFF on RANKL/OPG more deeply

is especially meaningful. We have known that

understood, but make positive bone remodeling more

osteoclastogenesis is inhibited under the FSS by

operational and more realistic.

decreasing RANKL/OPG mentioned by the first three

Tan and his colleagues [11] suggested that

researches, however, it has not been revealed what

osteocytes were the predominant bone cells and it was

happened to single osteoclast’s function when there was

generally accepted that the osteocytes were the

exposure to the FSS. More importantly, people may

professional mechanosensors of bone. Osteocytes

take it for granted that decrease in osteoclastogenesis is

produced high levels of nitric oxide (NO) in response to

equal to functional decline. We can see that the

FSS. High levels of NO have been shown to rapidly

conclusion may be totally reversed according to

reduce the osteoclast spread area followed by retraction

Zhang Q’s team’s experiments. The FSS restrains

of the cells from the tissues culture support and NO

osteoclastogenesis, and may increase osteolytic ability

donor treatment increased OPG expression of bone

of osteoclasts.

microenvironment in ovariectomized rats [12]. Researches have demonstrated that osteoclasts

3. M-CSF under hydrostatic pressure

dissolve the inorganic phase of the bones by secretion of






3.1. The function of M-CSF

calciumhydroxyapatite matrix. This process is also termed as demineralization. Zhang Q and his team[13]

Macrophage colony-stimulating factor (M-CSF),

found that this course in osteoclasts was stimulated by

also called colony stimulating factor 1 (CSF-1), is one

releasing specific carbonic anhydrasHĊ (CAĊ) into

of a family of growth factors. Its cellular effects are


Tong Xiaoyu et al./Journal of Medical Colleges of PLA 25(2010) 103-109

mediated via M-CSF receptor, which belongs to a


subfamily of the tyrosine kinase growth factor receptor.

extracellular matrix and increase the release of

Meanwhile, it is well known that M-CSF is strictly

resorption-stimulating factors. They have proved that



M-CSF production by osteoblasts in the joints where

osteoclasts [14]. Neale and his colleagues [15] found

stretch stimuli were loaded continuously could enhance

that in mouse marrow cultures, the addition of an anti-

osteoclast formation. However, little is known about

macrophage colony stimulating factor antibody had

how the level of M-CSF changes under the FSS.












been shown to partially inhibit the proliferation and completely inhibit the differentiation of osteoclast

4. Calcitonin receptor (CTR) under FSS

precursors. In addition, this antibody at the human commencement of co-culture inhibited the early stages

As osteoclast precursors differentiate and become

of osteoclast formation. Studies have suggested that

committed to the osteoclast lineage, they express high

M-CSF stimulated the biological activity of osteoclasts

levels of pp60c-src, carbonic anhydrase, and calcitonin

through a protein-tyrosine phosphorylation mechanism.

receptor [20]. CTR is a characteristic marker of

Moreover, M-CSF stimulation of bone marrow cells

osteoclasts, since it can be only found in osteoclasts or



osteoclast precursor. When calcitonin is bound to its

proliferating macrophage precursors [16]. Naokoet

receptor, the regulation of osteoclastic activity

[17] demonstrated that M-CSF inhibited both the OPG

and demineralization are inhibited. Baomin Z [21]

mRNA expression and the OPG secretion dose

suggested that the application of FSS resulted in a

dependently and reversibly, which might increase the

dose/time-dependent increase in CTR mRNA level.





sensitivity of bone marrow macrophages (BMMs) to RANKL.

Their specific achievements were: if the loading time was constant, relative to ten dyes FSS, increased CTR mRNA was more significant when it was under 3

3.2. The effect of mechanical-loading on M-CSF

dyes FSS, whereas CTR mRNA was increased with time if the loading power was unchanged. In our

In bone tissues, the forces were generated under

opinion, it was invaluable that researchers explained the

mechanical-loading such as pressure, strain, shear stress,

phenomenon which was contrary to their expectations.

and electric fields. Janet and his colleagues [18]

Baomin Z and his team found that the expression of

demonstrated that hydrostatic pressure might

cause a

CTR mRNA was reduced when the loading time was

decrease in mRNA coding for the membrane bound

fifteen minutes. Nevertheless, they suggested this result

form of M-CSF and therefore directly inhibited

was within the normal range since cells were under

proliferation or early events in osteoclast differentiation.

stress state due to short loading term. For the same

Moreover, Satoshi and his coworkers [19] suggested

reason, there existed an imbalance between synthesis

that continuous and high mechanical stimuli induced

and decomposition of CTR mRNA.

Tong Xiaoyu et al./Journal of Medical Colleges of PLA 25(2010) 103-109


Therefore, we conclude that the effect of FSS on

hematopoietic progenitor cells when they were

osteoclasts is not single. Such effect would be more

cocultured with osteoblasts/stromal cells in the

meaningful if we also take loading time, strength, etc.

presence of a systemic or local factor including VD3ˈ

into account.

PTH, PTH-related peptid, PGE2, IL-1, IL-6, IL-11, oncostatin M or leukemia inhibitory factor [22]. All of

5. Other relative factors

these osteoclast-inducing factors appear to act on osteoblastic cells to commonly induce ODF, which

There are various other factors which can enhance

recognizes osteoclast progenitors and prepares them to

osteoclast activity, such as 1,25-dihydroxyvitaminD3

differentiate into mature osteoclasts (Fig.1). That is

(VD3), parathyroidhormone (PTH), prostaglandinE2

they enhanced pit-forming activity of osteoclasts only

(PGE2), Interleukin11(IL-11) , TNFs (TNFa and TNFb),

in the presence of osteoblasts [23]. However, it is still

IL-6, IL-1, etc. Masazumi and Nobuko showed that

poorly understood currently how FSS influences these


factors, on which there is need for further investigation.




Fig.1. The factors that may affect osteoclastic formation.



Tong Xiaoyu et al./Journal of Medical Colleges of PLA 25(2010) 103-109


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