Skeletal Unloading Induces Resistance to Insulin-Like Growth Factor-I (IGF-I) by Inhibiting Activation of the IGF-I Signaling Pathways

Sakata, Toshiie; Wang, Yongmei; Halloran, Bernard P.; Elalieh, Hashem; Cao, Jay; Bikle, Daniel D.

doi:10.1359/jbmr.0301241

Cited by 104 publications

(116 citation statements)

References 57 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…We recently showed that fluid shear stress synergizes with IGF-I to stimulate Erk1/2 activation and osteoblast proliferation through integrin-dependent activation of the IGF-I signaling pathway (28), confirming a functional role of the IGF-I signaling pathway in the mechanical stimulation of osteoblast proliferation. Bikle and co-workers (26,27) have also demonstrated that skeletal unloading induces resistance to IGF-I to induce bone formation, which is caused by inhibition of the IGF-I signaling pathway through down-regulation of the integrin pathway. Regarding the ER signaling pathway, Lanyon and co-workers (25,(43)(44)(45)(46) have provided compelling evidence that ER, especially ER␣, is essential for mechanical stimulation of bone formation.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Lau

Kapur

Kesavan

et al. 2006

Journal of Biological Chemistry

150

138

View full text Add to dashboard Cite

C57BL/6J (B6), but not C3H/HeJ (C3H), mice responded to mechanical loading with an increase in bone formation. A 30-min steady fluid shear of 20 dynes/cm 2 increased [ 3 H]thymidine incorporation and alkaline phosphatase activity and up-regulated the expression of early mechanoresponsive genes (integrin ␤1 (Igtb1) and cyclooxygenase-2 (Cox-2)) in B6 but not C3H osteoblasts, indicating that the differential mechanosensitivity was intrinsic to osteoblasts. In-house microarray analysis with 5,500 gene fragments revealed that the expression of 669 genes in B6 osteoblasts and 474 genes in C3H osteoblasts was altered 4 h after the fluid shear. Several genes associated with the insulin-like growth factor (IGF)-I, the estrogen receptor (ER), the bone morphogenetic protein (BMP)/transforming growth factor-␤, and Wnt pathways were differentially up-regulated in B6 osteoblasts. In vitro mechanical loading also led to up-regulation of these genes in the bones of B6 but not C3H mice. Pretreatment of B6 osteoblasts with inhibitors of the Wnt pathway (endostatin), the BMP pathway (Noggin), or the ER pathway (ICI182780) blocked the fluid shear-induced proliferation. Inhibition of integrin and Cox-2 activation by echistatin and indomethacin, respectively, each blocked the fluid shear-induced up-regulation of genes associated with these four pathways. In summary, up-regulation of the IGF-I, ER, BMP, and Wnt pathways is involved in mechanotransduction. These four pathways are downstream to the early mechanoresponsive genes, i.e. Igtb1 and Cox-2. In conclusion, differential up-regulation of these anabolic pathways may in part contribute to the good and poor response, respectively, in the B6 and C3H mice to mechanical loading.Mechanical loading is essential for maintenance of skeletal architectural integrity. Loading stimulates bone formation and suppresses bone resorption, leading to an overall increase in bone mass (1), whereas unloading results in an overall decrease in bone mass, because of an inhibition of formation along with an increase in resorption (2). Loading produces strains in the mineralized matrix of bone, which generates interstitial fluid flow through lacunar/canalicular spaces (3). This fluid flow exerts a shear stress at surfaces of osteoblasts and osteocytes lining these spaces, which generates biochemical signals to produce biological effects. Multiple interacting signaling pathways are involved in translating the fluid shear signals into biological effects in bone cells (4), and these pathways are collectively referred to as the mechanotransduction mechanism. Mechanical loading is a key regulatory process for bone mass and strength (5). Knowledge of the mechanotransduction mechanism would not only yield information about the mechanical stimulation of bone formation but would also provide insights into the pathophysiology of osteoporosis and other bone-wasting diseases.There is increasing evidence that genetics play a major part in determining the bone response to mechanical loading. Studies from our group (6, 7...

show abstract

Section: Discussionmentioning

confidence: 99%

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Lau

Kapur

Kesavan

et al. 2006

Journal of Biological Chemistry

150

138

View full text Add to dashboard Cite

show abstract

“…Therefore, lack of reduction in bone formation by the loss of mechanical stress in the absent of OPN would be resulted in part in the loss of signals for differentiation of osteoblastic precursor cells in bone marrow cells. Recent data revealed that unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways through down-regulation of a v b 3 integrin in bone marrow cells (Sakata et al 2004). IGFbinding protein-5 (IGFBP-5), which is one of the six forms of IGFBPs, binds to OPN, and these interactions are considered to modulate the cooperative actions between the IGF-I receptor and integrin receptor signaling pathways (Nam et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin is required for mechanical stress-dependent signals to bone marrow cells

Ishijima¹,

Tsuji²,

Rittling³

et al. 2007

Journal of Endocrinology

View full text Add to dashboard Cite

Mechanical stress to bone plays a crucial role in the maintenance of bone homeostasis. It causes the deformation of bone matrix and generates strain force, which could initiate the mechanotransduction pathway. The presence of osteopontin (OPN), which is one of the abundant proteins in bone matrix, is required for the effects of mechanical stress on bone, as we have reported that OPN-null (OPNK/K) mice showed resistance to unloading-induced bone loss. However, cellular mechanisms underlying the phenomenon have not been completely elucidated. To obtain further insight into the role of OPN in mediating mechanical stress effect on bone, we examined in vitro mineralization and osteoclast-like cell formation in bone marrow cells obtained from hind limb bones of OPNK/K mice after tail suspension. The levels of mineralized nodule formation of bone marrow cells derived from the femora subjected to unloading were decreased compared with that from loaded control in wild-type mice. However, these were not decreased in cells from OPNK/K mice after tail suspension compared with that from loaded OPNK/K mice. Moreover, while spreading of osteoclast-like cells derived from bone marrow cells of the femora subjected to unloading was enhanced compared with that from loaded control in wild-type mice, this enhancement of spreading of these cells derived from the femora subjected to unloading was not recognized compared with those from loaded control in OPNK/K mice. These data provided cellular bases for the effect of the OPN deficiency on in vitro reduced mineralized nodule formation by osteoblasts and on enhancement of osteoclast spreading in vitro induced by the absence of mechanical stress. These in vitro results correlate well with the resistance to unloading-induced bone loss in OPNK/K mice in vivo, suggesting that OPN has an important role in the effects of unloading-induced alterations of differentiation of bone marrow into osteoblasts and osteoclasts.

show abstract

“…Plasma was obtained from blood from the facial vein of mice after 3-h fasting at the indicated age. P1NP and CTX were measured by using ELISA kits (Biomedical Technologies and Immunodiagnostic Systems), respectively (41,42,49). Alkaline phosphatase was measured on a Randox Daytona analyzer (Randox Laboratories Limited) at the General Clinical Research Center of Indiana University School of Medicine.…”

Section: Methodsmentioning

confidence: 99%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

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

237

View full text Add to dashboard Cite

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat Ot mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat Ot mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat Ot mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.osteocytes | canonical Wnt | beta-catenin | bone anabolism | notch signaling

show abstract

Skeletal Unloading Induces Resistance to Insulin-Like Growth Factor-I (IGF-I) by Inhibiting Activation of the IGF-I Signaling Pathways

Cited by 104 publications

References 57 publications

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Up-regulation of the Wnt, Estrogen Receptor, Insulin-like Growth Factor-I, and Bone Morphogenetic Protein Pathways in C57BL/6J Osteoblasts as Opposed to C3H/HeJ Osteoblasts in Part Contributes to the Differential Anabolic Response to Fluid Shear

Osteopontin is required for mechanical stress-dependent signals to bone marrow cells

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Contact Info

Product

Resources

About