Skeletal unloading in rat decreases proliferation of rat bone and marrow-derived osteoblastic cells

Machwate, Mohamed; Zérath, E.; Holy, Xavier; Hott, M.; Modrowski, Dominique; A, Malouvier; Marie, Pierre J.

doi:10.1152/ajpendo.1993.264.5.e790

Cited by 57 publications

(67 citation statements)

References 13 publications

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“…The cellular and molecular mechanisms involved in the decreased bone formation induced by skeletal unloading are, however, poorly understood. We previously reported that skeletal unloading induced by removal of weight bearing in rats is associated with impaired proliferation of osteoblast precursor cells in the marrow stroma (3). Unloading was also found to reduce the osteogenic capacity of osteoblast precursor cells in rat bone marrow (4).…”

Section: Introductionmentioning

confidence: 97%

Systemic administration of transforming growth factor-beta 2 prevents the impaired bone formation and osteopenia induced by unloading in rats.

Machwate¹,

Zérath²,

Holy³

et al. 1995

J. Clin. Invest.

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We investigated the effect of recombinant human transforming growth factor .82 (rhTGF-J32) administration on trabecular bone loss induced by unloading in rats. Hind limb suspension for 14 d inhibited bone formation and induced osteopenia as shown by decreased bone volume, calcium and protein contents in long bone metaphysis. Systemic infusion of rhTGF-P2 (2 jug/kg per day) maintained normal bone formation rate, and prevented the decrease in bone volume, bone mineral content, trabecular thickness and number induced by unloading. In vitro analysis of tibial marrow stromal cells showed that rhTGF-f32 infusion in unloaded rats increased the proliferation of osteoblast precursor cells, but did not affect alkaline phosphatase activity or osteocalcin production. Northern blot analysis of RNA extracted from the femoral metaphysis showed that rhTGF-fi2 infusion in unloaded rats increased steady-state levels of type I collagen mRNA but not alkaline phosphatase mRNA levels. rhTGF-P2 infusion at the dose used had no effect on metaphyseal bone volume and formation, osteoblast proliferation or collagen expression in control rats. The results show that systemic administration of rhTGF-l2 enhances osteoblast precursor cell proliferation and type I collagen expression by osteoblasts, and prevents the impaired bone formation and osteopenia induced by unloading. (J. Cln. Invest. 1995.

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Section: Introductionmentioning

confidence: 97%

Systemic administration of transforming growth factor-beta 2 prevents the impaired bone formation and osteopenia induced by unloading in rats.

Machwate¹,

Zérath²,

Holy³

et al. 1995

J. Clin. Invest.

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“…Emerging studies suggest that, like osteoblasts and osteocytes, MSCs are mechanoresponsive. MSCs isolated from rats after hindlimb unloading exhibit both a decreased proliferative potential and a reduced osteogenic capacity compared with loaded controls (39,74). Specifically, cells from these animals formed fewer mineralized and alkaline phosphatase-positive colonies in vitro, two commonly used markers of osteoblastic potential.…”

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confidence: 99%

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

Riddle

Taylor

Genetos

et al. 2006

American Journal of Physiology-Cell Physiology

169

136

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Although the mechanisms by which osteoblasts and osteocytes respond to fluid flow are being elucidated, little is known about the mechanisms by which bone marrow-derived mesenchymal stem cells respond to such stimuli. Here we show that the intracellular signaling cascades activated in human mesenchymal stem cells by fluid flow are similar to those activated in osteoblastic cells. Oscillatory fluid flow inducing shear stresses of 5, 10, and 20 dyn/cm 2 triggered rapid, flow rate-dependent increases in intracellular calcium that pharmacological studies suggest are inositol trisphosphate mediated. The application of fluid flow also induced the phosphorylation of extracellular signal-regulated kinase-1 and -2 as well as the activation of the calcium-sensitive protein phosphatase calcineurin in mesenchymal stem cells. Activation of these signaling pathways combined to induce a robust increase in cellular proliferation. These data suggest that mechanically induced fluid flow regulates not only osteoblastic behavior but also that of mesenchymal precursors, implying that the observed osteogenic response to mechanical loading may be mediated by alterations in the cellular behavior of multiple members of the osteoblast lineage, perhaps by a common signaling pathway. mechanotransduction; bone; marrow MAINTENANCE OF APPROPRIATE bone mass requires the coordination of bone resorption by osteoclasts and bone deposition by osteoblasts, and it is well established that mechanical stimuli can regulate the balance between bone formation and resorption. The addition of exogenous mechanical load is believed to stimulate new bone formation through increases in osteoblastic activity and concomitant decreases in osteoclastic activity (20). Conversely, removal of mechanical load, as is the case during spaceflight and disuse, leads to decreased osteoblastic activity and loss of bone mass (42,56).Accumulating evidence suggests that individual bone cells, including osteocytes and osteoblasts, are responsible for perceiving and responding to mechanical signals. Such signals, which may include streaming potentials, mechanical strain, and fluid shear stress, elicit a host of biochemical responses including mobilization of second messengers such as calcium (22,72), nitric oxide (26, 30), prostaglandins, and inositol trisphosphate (IP 3 ) (49); activation of kinase cascades including the MAP kinase and PKC pathways (44, 50); and modulation of gene expression (5, 46, 73). Strain-induced oscillatory fluid flow has been shown by our laboratory (73) and others (45) to be a potent biophysical stimulus. In MC3T3-E1 preosteoblasts, fluid flow induces the mobilization of intracellular calcium (Ca i 2ϩ ), activates ERK1/2, and increases osteopontin mRNA levels (11,72,73). Recent evidence has shown that exposing the osteocytic cell line MLO-Y4 to physiological levels of fluid flow induces similar responses (1, 6, 52).Although the mechanisms by which osteoblasts and osteocytes respond to mechanical stimuli are being elucidated, little is known about how bo...

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“…Emerging evidence suggests that bone marrow stromal cells (MSC), a focus of musculoskeletal tissue engineering resulting from the multipotent differentiation potential of this cell population, 95 are responsive to mechanical signals in a manner similar to osteoblasts and osteocytes. Following hindlimb suspension, an accepted model of skeletal unloading, MSCs isolated from rats exhibited a significant decrease in proliferation potential 96 as well as an impaired differentiation capacity. 97,98 Similar observations have been made following the isolation of MSCs from mice, 99 and reloading partially rescues deficits in MSC proliferation and differentiation.…”

Section: Fluid Flow In Tissue Engineeringmentioning

confidence: 99%

From streaming‐potentials to shear stress: 25 years of bone cell mechanotransduction

Riddle

Donahue

2008

Journal Orthopaedic Research

125

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Mechanical loads are vital regulators of skeletal mass and architecture as evidenced by the increase in bone formation following the addition of exogenous loads and loss of bone mass following their removal. While our understanding of the molecular mechanisms by which bone cells perceive changes in their mechanical environment has increased rapidly in recent years, much remains to be learned. Here, we outline the effects of interstitial fluid flow, a potent biophysical signal induced by the deformation of skeletal tissue in response to applied loads, on bone cell behavior. We focus on the molecular mechanisms by which bone cells are hypothesized to perceive interstitial fluid flow, the cell signaling cascades activated by fluid flow, and the use of this signal in tissue engineering protocols. ß

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Skeletal unloading in rat decreases proliferation of rat bone and marrow-derived osteoblastic cells

Cited by 57 publications

References 13 publications

Systemic administration of transforming growth factor-beta 2 prevents the impaired bone formation and osteopenia induced by unloading in rats.

Systemic administration of transforming growth factor-beta 2 prevents the impaired bone formation and osteopenia induced by unloading in rats.

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

From streaming‐potentials to shear stress: 25 years of bone cell mechanotransduction

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