Abstract
Summary
Histomorphometric assessment of trabecular bone in osteoporotic sheep showed that bone volume, osteoid surface area, bone formation rate, and osteocyte density were reduced. In contrast, eroded surface area and empty lacunae density were increased. Changes in osteocyte density correlated with changes in osteoblast and osteoclast activity.
Introduction
Osteocytes contribute to the regulation of the activity of osteoclasts and osteoblasts that together control bone mass. Osteocytes therefore likely play a role in the loss of bone mass associated with osteoporosis. The purpose of this study was to investigate the relationships between osteocyte lacunar density and other bone histomorphometric parameters in the iliac crest (IC) and lumbar spine (LS) of osteoporotic sheep.
Methods
Osteoporosis was induced in ten mature ewes by an established protocol involving a combination of ovariectomy, dexamethasone injection, and low calcium diet for 6 months. Five ewes were used as controls. Post-mortem IC and LS biopsies were collected and processed for further histomorphometric assessment.
Results
Bone volume, osteoid surface, and bone formation rate in the IC and LS of osteoporotic sheep were reduced compared to those of the controls. In contrast, eroded surface area was increased in osteoporotic sheep. In the osteoporotic group, osteocyte density was reduced in the LS region and to a greater extent in the IC region. The empty osteocyte lacunae were increased 1.7-fold in LS and 2.1-fold in IC in the osteoporotic group. The osteocyte density correlated positively with markers of osteoblast activity and negatively with those of osteoclast activity.
Conclusions
Depletion of osteocytes and an increase in the empty lacunae could be important factors contributing to bone loss in this model since they may adversely affect intercellular communication between osteoblasts and osteoclasts. The regional differences in histology suggest that there may be different pathological mechanisms operating at different anatomical sites.
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References
Ikeda K (2008) Osteocytes in the pathogenesis of osteoporosis. Geriatr Gerontol Int 8:213–217
Parfitt AM (2005) Modeling and remodeling: how bone cells work together. Elsevier, New York
Seeman E (2003) Invited review: pathogenesis of osteoporosis. J Appl Physiol 95:2142–2151
McDonnell P, McHugh PE, O'Mahoney D (2007) Vertebral osteoporosis and trabecular bone quality. Ann Biomed Eng 35:170–189
Seeman E (2006) Osteocytes–martyrs for integrity of bone strength. Osteoporos Int 17:1443–1448
Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869
Kamioka H, Honjo T, Takano-Yamamoto T (2001) A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy. Bone 28:145–149
Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26:229–238
Lanyon LE (1993) Osteocytes, strain detection, bone modeling and remodeling. Calcif Tissue Int 53:S102–S106, discussion S106-107
Noble BS, Stevens H, Loveridge N, Reeve J (1997) Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20:273–282
Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 24:1651–1661
O'Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841, Epub 2003 Dec 1822
Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP (2000) Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26:375–380
Qiu S, Rao DS, Palnitkar S, Parfitt AM (2003) Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res 18:1657–1663
Mikuni-Takagaki Y, Kakai Y, Satoyoshi M, Kawano E, Suzuki Y, Kawase T, Saito S (1995) Matrix mineralization and the differentiation of osteocyte-like cells in culture. J Bone Miner Res 10:231–242
Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/pre-osteocyte differentiation and regulates mineralization through a MEPE-ASARM dependent mechanism. J Bone Miner Res (in press)
McCreadie BR, Hollister SJ, Schaffler MB, Goldstein SA (2004) Osteocyte lacuna size and shape in women with and without osteoporotic fracture. J Biomech 37:563–572
Bonewald LF (2004) Osteocyte biology: its implications for osteoporosis. J Musculoskelet Neuronal Interact 4:101–104
Emerton KB, Hu B, Woo AA, Sinofsky A, Hernandez C, Majeska RJ, Jepsen KJ, Schaffler MB (2010) Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 46:577–583, Epub 2009 Nov 2017
Gaudio A, Pennisi P, Bratengeier C, Torrisi V, Lindner B, Mangiafico RA, Pulvirenti I, Hawa G, Tringali G, Fiore CE (2010) Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 95:2248–2253
Skedros JG, Grunander TR, Hamrick MW (2005) Spatial distribution of osteocyte lacunae in equine radii and third metacarpals: considerations for cellular communication, microdamage detection and metabolism. Cells Tissues Organs 180:215–236
Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615, Epub 2008 Jan 2012
Zarrinkalam MR, Beard H, Schultz CG, Moore RJ (2009) Validation of the sheep as a large animal model for the study of vertebral osteoporosis. Eur Spine J 18:244–253
Veigel E, Moore RJ, Zarrinkalam MR, Schulze D, Sauerbier S, Schmelzeisen R, Voss PJ (2011) Osteopenia in the maxillofacial area: a study in sheep. Osteoporos Int 22:1115
Zarrinkalam MR, Schultz CG, Parkinson IH, Moore RJ (2009) Osteoporotic characteristics remain in the vertebrae of osteoporotic sheep after cessation of corticosteroid administration. In: Annual Scientific Meeting of the Spine Society of Australia. Brisbane, Australia
Anderson PH, Hendrix I, Sawyer RK, Zarrinkalam R, Manavis J, Sarvestani GT, May BK, Morris HA (2008) Co-expression of CYP27B1 enzyme with the 1.5 kb CYP27B1 promoter-luciferase transgene in the mouse. Mol Cell Endocrinol 285:1–9, Epub 2008 Jan 2016
Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610
Qiu S, Rao DS, Palnitkar S, Parfitt AM (2002) Age and distance from the surface but not menopause reduce osteocyte density in human cancellous bone. Bone 31:313–318
Chappard D, Legrand E, Basle MF, Fromont P, Racineux JL, Rebel A, Audran M (1996) Altered trabecular architecture induced by corticosteroids: a bone histomorphometric study. J Bone Miner Res 11:676–685
Nakamuta H, Nitta T, Hoshino T, Koida M (1996) Glucocorticoid-induced osteopenia in rats: histomorphometrical and microarchitectural characterization and calcitonin effect. Biol Pharm Bull 19:217–219
Aaron JE, Makins NB, Sagreiya K (1987) The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop Relat Res 260–271
Weinstein RS, Manolagas SC (2000) Apoptosis and osteoporosis. Am J Med 108:153–164
Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, Kinney JH, Bonewald LF (2006) Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res 21:466–476, Epub 2005 Nov 2014
Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137
Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282
Chavassieux PM, Arlot ME, Roux JP, Portero N, Daifotis A, Yates AJ, Hamdy NA, Malice MP, Freedholm D, Meunier PJ (2000) Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies. J Bone Miner Res 15:754–762
Dalle Carbonare L, Arlot ME, Chavassieux PM, Roux JP, Portero NR, Meunier PJ (2001) Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 16:97–103
Mullender MG, van der Meer DD, Huiskes R, Lips P (1996) Osteocyte density changes in aging and osteoporosis. Bone 18:109–113
Abad V, Chrousos GP, Reynolds JC, Nieman LK, Hill SC, Weinstein RS, Leong GM (2001) Glucocorticoid excess during adolescence leads to a major persistent deficit in bone mass and an increase in central body fat. J Bone Miner Res 16:1879–1885
Hedgecock NL, Hadi T, Chen AA, Curtiss SB, Martin RB, Hazelwood SJ (2007) Quantitative regional associations between remodeling, modeling, and osteocyte apoptosis and density in rabbit tibial midshafts. Bone 40:627–637, Epub 2006 Dec 2008
Mori S, Harruff R, Ambrosius W, Burr DB (1997) Trabecular bone volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures. Bone 21:521–526
Verborgt O, Gibson GJ, Schaffler MB (2000) Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 15:60–67
Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB (2009) Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J Bone Miner Res 24:597–605
Mann V, Huber C, Kogianni G, Jones D, Noble B (2006) The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone. J Musculoskelet Neuronal Interact 6:408–417
Qiu S, Rao DS, Palnitkar S, Parfitt AM (2006) Differences in osteocyte and lacunar density between Black and White American women. Bone 38:130–135, Epub 2005 Aug 2019
Seeman E (2008) Structural basis of growth-related gain and age-related loss of bone strength. Rheumatol (Oxf) 47:iv2-8
Braith RW, Magyari PM, Fulton MN, Aranda J, Walker T, Hill JA (2003) Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients. J Heart Lung Transplant 22:1082–1090
Westerlind KC, Fluckey JD, Gordon SE, Kraemer WJ, Farrell PA, Turner RT (1998) Effect of resistance exercise training on cortical and cancellous bone in mature male rats. J Appl Physiol 84:459–464
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Zarrinkalam, M.R., Mulaibrahimovic, A., Atkins, G.J. et al. Changes in osteocyte density correspond with changes in osteoblast and osteoclast activity in an osteoporotic sheep model. Osteoporos Int 23, 1329–1336 (2012). https://doi.org/10.1007/s00198-011-1672-4
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DOI: https://doi.org/10.1007/s00198-011-1672-4