[en] This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by crossbreeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (similar to 1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone beta-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity.
Kesavan, Chandrasekhar; Jerry L Pettis Mem Vet Affairs Med Ctr, Musculoskeletal Dis Ctr, Loma Linda, CA USA.
Sheng, Matilda H.-C.; Loma Linda Univ, Sch Med, Dept Med, Div Regenerat Med, Loma Linda, CA 92350 USA.
Language :
English
Title :
Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity
Publication date :
2013
Journal title :
American Journal of Physiology - Endocrinology and Metabolism
ISSN :
0193-1849
eISSN :
1522-1555
Publisher :
Amer Physiological Soc, Bethesda, United States - Maryland
Volume :
305
Issue :
2
Pages :
E271-E281
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Telemedicine and Advanced Technology Research Center (TATRC) at the US Army Medical Research and Material Command (USAMRMC) [W81XWH-08-1-0697]
Commentary :
The work is supported by the Telemedicine and Advanced Technology Research Center (TATRC) at the US Army Medical Research and Material Command (USAMRMC) under Grant No. W81XWH-08-1-0697. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.
Akhter, M.P., Cullen, D.M., Pedersen, E.A., Kimmel, D.B., Recker, R.R., Bone response to in vivo mechanical loading in two breeds of mice (1998) Calcif Tissue Int, 63, pp. 442-449
Bafico, A., Gazit, A., Pramila, T.M., Finch, P.W., Yaniv, A., Aaronson, S.A., Interaction of frizzled related protein (FRP) with wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of wnt signaling (1999) J Biol Chem, 274, pp. 16180-16187
Bass, S.L., Saxon, L., Daly, R.M., Turner, C.H., Robling, A.G., Seeman, E., Stuckey, S., The effect of mechanical loading on the size and shape of bone in pre-, peri-, and postpubertal girls: A study in tennis players (2002) J Bone Miner Res, 17, pp. 2274-2280
Brun, J., Fromigue, O., Dieudonne, F.X., Marty, C., Chen, J., Dahan, J., Wei, Y., Marie, P.J., The LIM-only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through Wnt5a and Wnt10b (2013) Bone, 53, pp. 6-12
Cawthorn, W.P., Bree, A.J., Yao, Y., Du, B., Hemati, N., Martinez-Santibanez, G., McDougald, O.A., Wnt6, wnt10a and wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism (2012) Bone, 50, pp. 477-489
Chambers, T.J., Fox, S., Jagger, C.J., Lean, J.M., Chow, J.W., The role of prostaglandins and nitric oxide in the response of bone to mechanical forces (1999) Osteoarthritis Cartilage, 7, pp. 422-423
Chen, R.H., Ding, W.V., McCormick, F., Wnt signaling to beta-catenin involves two interactive components. Glycogen synthase kinase-3beta inhibition and activation of protein kinase C (2000) J Biol Chem, 275, pp. 17894-17899
Christiansen, B.A., Kotiya, A.A., Silva, M.J., Constrained tibial vibration does not produce an anabolic bone response in adult mice (2009) Bone, 45, pp. 750-759
Courtwright, A., Siamakpour-Reihani, S., Arbiser, J.L., Banet, N., Hilliard, E., Fried, L., Livasy, C., Klauber-Demore, N., Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (2009) Cancer Res, 69, pp. 4621-4628
Cowin, S.C., (2001) Bone Mechanics Hand Book, , (2nd Ed.). Washington, DC: CRC Press
Esteve, P., Sandonis, A., Ibanez, C., Shimono, A., Guerrero, I., Bovolenta, P., Secreted frizzled-related proteins are required for wnt/β-catenin signaling activation in the vertebrate optic cup (2011) Development, 138, pp. 4179-4184
Fedi, P., Bafico, A., Nieto Soria, A., Burgess, W.H., Miki, T., Bottaro, D.P., Kraus, M.H., Aaronson, S.A., Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian wnt signaling (1999) J Biol Chem, 274, pp. 19465-19472
Gaston, J., Quinchia Rios, B., Bartlett, R., Berchtold, C., Thibeault, S.L., The response of vocal fold fibroblasts and mesenchymal stromal cells to vibration (2012) PLoS One, 7, pp. e30965
Grimston, S.K., Goldberg, D.B., Watkins, M., Brodt, M.D., Silva, M.J., Civitelli, R., Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis (2011) J Bone Miner Res, 26, pp. 2151-2160
Hara, M., Tabata, K., Suzuki, T., Do, M.K., Mizunoya, W., Nakamura, M., Nishimura, S., Tatsumi, R., Calcium influx through a possible coupling of cation channels impacts skeletal muscle satellite cell activation in response to mechanical stretch (2012) Am J Physiol Cell Physiol, 302, pp. C1741-C1750
Hsieh, H.J., Li, N.Q., Frangos, J.A., Pulsatile and steady flow induces c-fos expression in human endothelial cells (1993) J Cell Physiol, 154, pp. 143-151
Ishihara, Y., Sugawara, Y., Kamioka, H., Kawanabe, N., Hayano, S., Balam, T.A., Naruse, K., Yamashiro, T., Ex vivo real-time observation of Ca2+ signaling in living bone in response to shear stress applied on the bone surface (2013) Bone, 53, pp. 204-215
Kamioka, H., Honjo, T., Takano-Yamamoto, T., A three-dimentional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy (2001) Bone, 28, pp. 145-149
Kamioka, H., Ishiharra, Y., Ris, H., Murshid, S.A., Sugawara, Y., Takano-Yamamoto, T., Lim, S.S., Primary cultures of chick osteocytes retain functional gap junctions between osteocytes and between osteocytes and osteoblasts (2007) Microsc Microanal, 13, pp. 108-117
Kapur, S., Amoui, M., Kesavan, C., Wang, X., Mohan, S., Baylink, D.J., Lau, K.H.W., Leptin receptor (Lepr) is a negative modulator of bone mechanosensitivity and genetic variations in Lepr may contribute to the differential osteogenic response to mechanical stimulation in the C57BL/6J and C3H/HeJ pair of mouse strains (2010) J Biol Chem, 285, pp. 37607-37618
Kapur, S., Baylink, D.J., Lau, K.H.W., Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways (2003) Bone, 32, pp. 241-251
Kapur, S., Mohan, S., Baylink, D.J., Lau, K.H.W., Fluid shear stress synergizes with insulin-like growth factor-I (IGF-I) on osteoblast proliferation through integrin-dependent activation of IGF-I mitogenic signaling pathway (2005) J Biol Chem, 280, pp. 20163-20170
Kawata, A., Mikuni-Takagaki, Y., Mechanotransduction in stretched osteocytes-temporal expression of immediate early and other genes (1998) Biochem Biophys Res Commun, 246, pp. 404-408
Kele, J., Andersson, E.R., Villaescusa, J.C., Cajanek, L., Parish, C.L., Bonilla, S., Toledo, E.M., Arenas, E., SFRP1 and SFRP2 does-dependently regulate midbrain dopamine neuron development in vivo and in embryonic stem cells (2012) Stem Cells, 30, pp. 865-875
Kesavan, C., Wergedal, J.E., Lau, K.H.W., Mohan, S., Conditional disruption of IGF-I gene in type 1α collagen-expressing cells shows an essential role of IGF-I in skeletal anabolic response to loading (2011) Am J Physiol Endocrinol Metab, 301, pp. E1191-E1197
Kim, S.W., Pajevic, P.D., Selig, M., Barry, K.J., Yang, J.Y., Shin, C.S., Baek, W.Y., Kronenberg, H.M., Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts (2012) J Bone Miner Res, 27, pp. 2075-2084
Klein-Nulend, J., Semeins, C.M., Ajubi, N.E., Nijweide, P.J., Burger, E.H., Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts-correlation with prostaglandin upregulation (1995) Biochem Biophy Res Commun, 217, pp. 640-648
Klein-Nulend, J., Van der Plas, A., Semeins, C.M., Ajubi, N.E., Frangos, J.A., Nijweide, P.J., Burger, E.H., Sensitivity of osteocytes to biomechanical stress in vitro (1995) FASEB J, 9, pp. 441-445
Kodama, Y., Umemura, Y., Nagasawa, S., Beamer, W.G., Donahue, L.R., Rosen, C.R., Baylink, D.J., Farley, J.R., Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J mice but not in C3H/HeJ mice (2000) Calcif Tissue Int, 66, pp. 298-306
Kohler, T., Beyeler, M., Webster, D., Müller, R., Compartmental bone morphometry in the mouse femur: Reproducibility and resolution dependence of microtomographic measurements (2005) Calcif Tissue Int, 77, pp. 281-290
Kohler, T., Stauber, M., Donahue, L.R., Müller, R., Automated compartmental analysis for high-throughput skeletal phenotyping in femora of genetic mouse models (2007) Bone, 41, pp. 659-667
Lean, J.M., Jagger, C.J., Chambers, T.J., Chow, J.W.M., Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation (1995) Am J Physiol Endocrinol Metab, 268, pp. E318-E327
Lean, J.M., McKay, A.G., Chow, J.W.M., Chambers, T.J., Osteocytic expression of mRNA for c-fos and IGF-I: An immediate early response to an osteogenic stimulus (1996) Am J Physiol Endocrinol Metab, 270, pp. E937-E945
Li, X., Zhang, Y., Kang, H., Liu, W., Liu, P., Zhang, J., Harris, S.E., Wu, D., Sclerostin binds to LRP5/6 and antagonizes canonical wnt signaling (2005) J Biol Chem, 280, pp. 19883-19887
Liu, C., Li, Y., Semenov, M., Han, C., Baeq, G.H., Tan, Y., Zhang, Z., He, X., Control of beta-catenin phosphorylation/degradation by a dualkinase mechanism (2002) Cell, 108, pp. 837-847
Lu, X.L., Huo, B., Chiang, V., Guo, X.E., Osteocytic network is more responsive in calcium signaling than osteoblastic network under fluid flow (2012) J Bone Miner Res, 27, pp. 563-574
Main, R.P., Lynch, M.E., van der Meulen, M.C.H., In vivo tibial stiffness is maintained by whole bone morphology and cross-sectional geometry in growing female mice (2010) J Biomech, 43, pp. 2689-2694
Mao, B., Wu, W., Davidson, G., Marhold, J., Li, M., Mechler, B.M., Delius, H., Niehrs, C., Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signaling (2002) Nature, 417, pp. 664-667
Mason, D.J., Hillam, R.A., Skerry, T.M., Constitutive in vivo mRNA expression by osteocytes of beta-actin, osteocalcin, connexin-43, IGF-I, c-fos and c-jun, but not TNF-alpha nor tartrate-resistant acid phosphatase (1996) J Bone Miner Res, 11, pp. 350-357
Mii, Y., Taira, M., Secreted wnt "inhibitors" are not just inhibitors: Regulation of extracellular wnt by secreted frizzled-related proteins (2011) Dev Growth Differ, 53, pp. 911-923
Mikuni-Takagaki, Y., Mechanical responses and signal transduction pathways in stretched osteocytes (1999) J Bone Miner Metab, 17, pp. 57-60
Mohan, S., Baylink, D.J., Bone growth factors (1991) Clin Orthop Relat Res, 263, pp. 30-38
Papachristou, D.J., Papachroni, K.K., Papavassiliou, G.A., Pirttiniemi, P., Gorgoulis, V.G., Piperi, C., Basdra, E.K., Functional alterations in mechanical loading of condylar cartilage induces changes in the bony subcondylar region (2009) Arch Oral Biol, 54, pp. 1035-1045
Powell Jr., W.F., Barry, K.J., Tulum, I., Kobayashi, T., Harris, S.E., Bringhurst, F.R., Pajevic, P.D., Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses (2011) J Endocrinol, 209, pp. 21-32
Qiao, M., Shapiro, P., Kumar, R., Passaniti, A., Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Akt-independent signaling pathway (2004) J Biol Chem, 279, pp. 42709-42718
Radcliff, K., Tang, T.B., Lim, J., Zhang, Z., Abedin, M., Demer, L.L., Tintut, Y., Insulin-like growth factor regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways (2005) Circ Res, 96, pp. 398-400
Reijnders, C.M.A., Bravenboer, N., Tromp, A.M., Blankenstein, M.A., Lips, P., Effect of mechanical loading on insulin-like growth factor-I gene expression in rat tibia (2007) J Endocrinol, 192, pp. 131-140
Robinson, J.A., Chatterjee-Kishore, M., Yaworsky, P.J., Cullen, D.M., Zhao, W., Li, C., Kharode, Y., Bex, F.J., Wnt/β-catenin signaling is a normal physiological response to mechanical loading in bone (2006) J Biol Chem, 281, pp. 31720-31728
Robling, A.G., Niziolek, P.J., Baldridge, L.A., Condon, K.W., Allen, M.R., Alam, I., Mantila, S.M., Turner, C.H., Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/Sclerostin (2008) J Biol Chem, 283, pp. 5866-5875
Rubin, C.T., Gross, T.S., McLeod, K.J., Bain, S.D., Morphologic stages in lamellar bone formation stimulated by a potent mechanical stimulus (1995) J Bone Miner Res, 10, pp. 488-495
Sakata, T., Halloran, B.P., Elalieh, H.Z., Munson, S.J., Rudner, L., Venton, L., Ginzinger, D., Bikle, D.D., Skeletal unloading induces resistance to insulin-like growth factor I on bone formation (2003) Bone, 32, pp. 669-680
Sakata, T., Wang, Y., Halloran, B.P., Elalieh, H.Z., Cao, J., Bikle, D.D., Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways (2004) J Bone Miner Res, 19, pp. 235-244
Sheng, M.H.C., Lau, K.H.W., Beamer, W.G., Baylink, D.J., Wergedal, J.E., In vivo and in vitro evidence that the high osteoblastic activity in C3H/HeJ mice compared to C57BL/6J mice is intrinsic to bone cells (2004) Bone, 35, pp. 711-719
Sheng, M.H.C., Zhou, X.D., Bonewald, L.F., Baylink, D.J., Lau, K.H.W., Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice (2013) Bone, 52, pp. 133-144
Sobiesiak, M., Sivasubramaniyan, K., Hermann, C., Tan, C., Orgel, M., Treml, S., Cerabona, F., Bühring, H.J., The mesenchymal stem cell antigen MSCA-1 is identical to tissue non-specific alkaline phosphatase (2010) Stem Cells Dev, 19, pp. 669-677
Soria, B., Navas, S., Hmadcha, A., Hamill, O.P., Single mechanosensitive and Ca2+-sensitive channel currents recorded from mouse and human embryonic stem cells (2013) J Membr Biol, 246, pp. 215-230
Tatsumi, S., Ishii, K., Amizuka, N., Li, M., Kobayashi, T., Kokno, K., Ito, M., Kyoji, I., Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction (2007) Cell Metab, 5, pp. 464-485
Temiyasathit, S., Tang, W.J., Leucht, P., Anderson, C.T., Monica, S.D., Castillo, A.B., Helms, J.A., Jacobs, C.R., Mechanosensing by the primary cilium: Deletion of kif3A reduces bone formation due to loading (2012) PLoS ONE, 7, pp. e33368
Tu, X., Rhee, Y., Condon, K.W., Bivi, N., Allen, M.R., Dwyer, D., Stolina, M., Bellido, T., Sost downregulation and local wnt signaling are required for the osteogenic response to mechanical loading (2012) Bone, 50, pp. 209-217
Turner Bone strength: Current concepts CH (2006) Ann NY Acad Sci, 1068, pp. 429-446
Turner, C.H., Forwood, M.R., Rho, J.Y., Yoshikawa, T., Mechanical loading thresholds for lamellar and woven bone formation (1994) J Bone Miner Res, 9, pp. 87-97
von Marschall, Z., Fisher, L.W., Secreted frizzled-regulated protein-2 (sFRP2) augments canonical wnt3a-induced signaling (2010) Biochem Biophy Res Commun, 400, pp. 299-304
Wergedal, J.E., Mohan, S., Lundy, M., Baylink, D.J., Skeletal growth factor and other growth factors known to be present in bone matrix stimulate proliferation and protein synthesis in human bone cells (1990) J Bone Miner Res, 5, pp. 179-186
Winkler, D.G., Sutherland, M.S., Ojala, E., Turcott, E., Geoghegan, J.C., Shpektor, D., Skonier, J.E., Latham, J.A., Sclerostin inhibition of wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins (2005) J Biol Chem, 280, pp. 2498-2502
Xiao, Z., Dallas, M., Qin, N., Nicolella, D., Cao, L., Johnson, M., Boneward, L., Quarles, L.D., Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice (2011) FASEB J, 25, pp. 1-15
Zhou, H., Newnum, A.B., Martin, J.R., Li, P., Nelson, M.T., Moh, A., Fu, X.Y., Li, J., Osteoblast/osteocyte-specific inactivation of Stat3 decreases load-driven bone formation and accumulates reactive oxygen species (2011) Bone, 49, pp. 404-411