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Osteoporosis International

Published in:

01-02-2016 | Original Article

Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals

Authors: D. Krishnamoorthy, D. M. Frechette, B. J. Adler, D. E. Green, M. E. Chan, C. T. Rubin

Published in: Osteoporosis International | Issue 2/2016

Abstract

Summary

Ovariectomized mice were used to assess the ability of low-intensity vibrations to protect bone microarchitecture and marrow composition. Results indicate that low-intensity vibrations (LIV), introduced 2 weeks postsurgery, slows marrow adipogenesis in OVX mice but does not restore the bone within the period studied. However, immediate application of LIV partially protects quality.

Introduction

The aim of this study was to evaluate consequences of estrogen depletion on bone marrow (BM) phenotype and bone microarchitecture, and effects of mechanical signals delivered as LIV on modulating these changes.

Methods

LIV (0.3 g, 90 Hz) was applied to C57BL/6 mice immediately following ovariectomy or 2 weeks postestrogen withdrawal for 2 (ST-LIV) or 6 weeks (LT-LIV), respectively. Sham-operated age-matched controls (ST-AC, LT-AC) and ovariectomized controls (ST-OVX, LT-OVX) received sham LIV treatment. Bone microstructure was evaluated through μCT and BM adipogenesis through histomorphometry, serum markers, and genes expression analysis.

Results

LT-OVX increased BM adipogenesis relative to LT-AC (+136 %, p ≤ 0.05), while LT-LIV introduced for 6w suppressed this adipose encroachment (−55 %, p ≤ 0.05). In parallel with the fatty marrow, LT-OVX showed a marked loss of trabecular bone, −40 % (p ≤ 0.05) in the first 2 weeks following ovariectomy compared to LT-AC. Application of LT-LIV for 6w following this initial 2w bone loss failed to restore the lost trabeculae but did initiate an anabolic response as indicated by increased serum alkaline phosphatase (+26 %, p ≤ 0.05). In contrast, application of LIV immediately following ovariectomy was more efficacious in the protection of trabecular bone, with a +29 % (p > 0.05) greater BV/TV compared to ST-OVX at the 2w time period.

Conclusions

LIV can mitigate adipocyte accumulation in OVX marrow and protect it by favoring osteoblastogenesis over adipogenesis. These data also emphasize the rapidity of bone loss with OVX and provide perspective in the timing of treatments for postmenopausal osteoporosis where sooner is better than later.

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Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B (2014) The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29(11):2520–2526. doi:10.1002/jbmr.2269 CrossRefPubMed

Gallagher JC, Goldgar D, Moy A (1987) Total bone calcium in normal women: effect of age and menopause status. J Bone Miner Res 2(6):491–496. doi:10.1002/jbmr.5650020605 CrossRefPubMed

Endicott RD (2013) Knowledge, health beliefs, and self-efficacy regarding osteoporosis in perimenopausal women. J Osteoporos 2013:853531. doi:10.1155/2013/853531 PubMedCentralCrossRefPubMed

Khosla S, Oursler MJ, Monroe DG (2012) Estrogen and the skeleton. Trends Endocrinol Metab 23(11):576–581. doi:10.1016/j.tem.2012.03.008 PubMedCentralCrossRefPubMed

Lerner UH (2006) Bone remodeling in post-menopausal osteoporosis. J Dent Res 85(7):584–595CrossRefPubMed

Palacios S, Mejia A (2015) Antiresorptives and anabolic therapy in sequence or combination for postmenopausal osteoporosis. Climacteric:1–3. doi:10.3109/13697137.2015.1016378

Delmas PD (2002) Treatment of postmenopausal osteoporosis. Lancet 359(9322):2018–2026. doi:10.1016/S0140-6736(02)08827-X CrossRefPubMed

Body JJ, Bergmann P, Boonen S, Boutsen Y, Bruyere O, Devogelaer JP, Goemaere S, Hollevoet N, Kaufman JM, Milisen K, Rozenberg S, Reginster JY (2011) Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club. Osteoporos Int 22(11):2769–2788. doi:10.1007/s00198-011-1545-x PubMedCentralCrossRefPubMed

Nadal-Casellas A, Proenza AM, Llado I, Gianotti M (2011) Effects of ovariectomy and 17-beta estradiol replacement on rat brown adipose tissue mitochondrial function. Steroids 76(10–11):1051–1056. doi:10.1016/j.steroids.2011.04.009 CrossRefPubMed

10.

Teede HJ, Lombard C, Deeks AA (2010) Obesity, metabolic complications and the menopause: an opportunity for prevention. Climacteric 13(3):203–209. doi:10.3109/13697130903296909 CrossRefPubMed

11.

Gaspard U (2009) Hyperinsulinaemia, a key factor of the metabolic syndrome in postmenopausal women. Maturitas 62(4):362–365. doi:10.1016/j.maturitas.2008.11.026 CrossRefPubMed

12.

Ludgero-Correia A Jr, Aguila MB, Mandarim-de-Lacerda CA, Faria TS (2011) Effects of high-fat diet on plasma lipids, adiposity, and inflammatory markers in ovariectomized C57BL/6 mice. Nutrition. doi:10.1016/j.nut.2011.07.014 PubMed

13.

Benayahu D, Shur I, Ben-Eliyahu S (2000) Hormonal changes affect the bone and bone marrow cells in a rat model. J Cell Biochem 79(3):407–415CrossRefPubMed

14.

Chen TY, Zhang ZM, Zheng XC, Wang L, Huang MJ, Qin S, Chen J, Lai PL, Yang CL, Liu J, Dai YF, Jin DD, Bai XC (2013) Endogenous n-3 polyunsaturated fatty acids (PUFAs) mitigate ovariectomy-induced bone loss by attenuating bone marrow adipogenesis in FAT1 transgenic mice. Drug Des Devel Ther 7:545–552. doi:10.2147/DDDT.S45263 PubMedCentralPubMed

15.

Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM (2009) Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 19(2):109–124PubMedCentralCrossRefPubMed

16.

Luu YK, Capilla E, Rosen CJ, Gilsanz V, Pessin JE, Judex S, Rubin CT (2009) Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J Bone Miner Res 24(1):50–61. doi:10.1359/jbmr.080817 PubMedCentralCrossRefPubMed

17.

Rubin CT, Capilla E, Luu YK, Busa B, Crawford H, Nolan DJ, Mittal V, Rosen CJ, Pessin JE, Judex S (2007) Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc Natl Acad Sci U S A 104(45):17879–17884. doi:10.1073/Pnas.0708467104 PubMedCentralCrossRefPubMed

18.

Judex S, Lei X, Han D, Rubin C (2007) Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J Biomech 40(6):1333–1339. doi:10.1016/j.jbiomech.2006.05.014 CrossRefPubMed

19.

Chan ME, Adler BJ, Green DE, Rubin CT (2012) Bone structure and B-cell populations, crippled by obesity, are partially rescued by brief daily exposure to low-magnitude mechanical signals. Faseb J 26(12):4855–4863. doi:10.1096/fj.12-209841 PubMedCentralCrossRefPubMed

20.

Lublinsky S, Ozcivici E, Judex S (2007) An automated algorithm to detect the trabecular-cortical bone interface in micro-computed tomographic images. Calcif Tissue Int 81(4):285–293. doi:10.1007/s00223-007-9063-8 CrossRefPubMed

21.

Carola Krause DJJdG, Marcel Karperien, Peter ten Dijke (2008) Signal transduction cascades controlling osteoblast differentiation. In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research. John Wiley & Sons, pp 10–16

22.

Brun RP, Spiegelman BM (1997) PPAR gamma and the molecular control of adipogenesis. J Endocrinol 155(2):217–218CrossRefPubMed

23.

Elbaz A, Rivas D, Duque G (2009) Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice. Biogerontology 10(6):747–755. doi:10.1007/s10522-009-9221-7 CrossRefPubMed

24.

Gevers EF, Loveridge N, Robinson IC (2002) Bone marrow adipocytes: a neglected target tissue for growth hormone. Endocrinology 143(10):4065–4073CrossRefPubMed

25.

Martin RB, Zissimos SL (1991) Relationships between marrow fat and bone turnover in ovariectomized and intact rats. Bone 12(2):123–131CrossRefPubMed

26.

Ozcivici E, Luu YK, Rubin CT, Judex S (2010) Low-level vibrations retain bone marrow’s osteogenic potential and augment recovery of trabecular bone during reambulation. PLoS One 5(6), e11178. doi:10.1371/journal.pone.0011178 PubMedCentralCrossRefPubMed

27.

Tanizawa T, Yamaguchi A, Uchiyama Y, Miyaura C, Ikeda T, Ejiri S, Nagal Y, Yamato H, Murayama H, Sato M, Nakamura T (2000) Reduction in bone formation and elevated bone resorption in ovariectomized rats with special reference to acute inflammation. Bone 26(1):43–53CrossRefPubMed

28.

Sakakura Y, Shide N, Tsuruga E, Irie K, Yajima T (2001) Effects of running exercise on the mandible and tibia of ovariectomized rats. J Bone Miner Metab 19(3):159–167CrossRefPubMed

29.

Flieger J, Karachalios T, Khaldi L, Raptou P, Lyritis G (1998) Mechanical stimulation in the form of vibration prevents postmenopausal bone loss in ovariectomized rats. Calcif Tissue Int 63(6):510–514CrossRefPubMed

30.

Ohlsson C, Engdahl C, Fak F, Andersson A, Windahl SH, Farman HH, Moverare-Skrtic S, Islander U, Sjogren K (2014) Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9(3), e92368. doi:10.1371/journal.pone.0092368 PubMedCentralCrossRefPubMed

31.

Lane NE, Haupt D, Kimmel DB, Modin G, Kinney JH (1999) Early estrogen replacement therapy reverses the rapid loss of trabecular bone volume and prevents further deterioration of connectivity in the rat. J Bone Miner Res 14(2):206–214. doi:10.1359/jbmr.1999.14.2.206 CrossRefPubMed

32.

Zhang R, Gong H, Zhu D, Gao J, Fang J, Fan Y (2014) Seven day insertion rest in whole body vibration improves multi-level bone quality in tail suspension rats. PLoS One 9(3), e92312. doi:10.1371/journal.pone.0092312 PubMedCentralCrossRefPubMed

33.

Sen B, Xie Z, Case N, Styner M, Rubin CT, Rubin J (2011) Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen. J Biomech 44(4):593–599. doi:10.1016/j.jbiomech.2010.11.022 PubMedCentralCrossRefPubMed

34.

Adler BJ, Kaushansky K, Rubin CT (2014) Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nat Rev Endocrinol 10(12):737–748. doi:10.1038/nrendo.2014.169 CrossRefPubMed

35.

Pino AM, Rosen CJ, Rodriguez JP (2012) In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Biol Res 45(3):279–287. doi:10.1590/S0716-97602012000300009 CrossRefPubMed

36.

Kai-Chiang Yang K-CY, Huang J-Y, Wu C-C, Lin F-H (2011) Sintered dicalcium pyrophosphate decreases bone turnover rate in osteoporotic rat: a study on serum biochemical bone turnover markers. Biomed Aging Pathol 1:45–51. doi:10.1016/j.biomag.2010.10.004

37.

Miyazaki T, Matsunaga T, Miyazaki S, Hokari S, Komoda T (2004) Changes in receptor activator of nuclear factor-kappaB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats. J Cell Biochem 93(3):503–512. doi:10.1002/jcb.20201 CrossRefPubMed

38.

Garcia-Perez MA, Noguera I, Hermenegildo C, Martinez-Romero A, Tarin JJ, Cano A (2006) Alterations in the phenotype and function of immune cells in ovariectomy-induced osteopenic mice. Hum Reprod 21(4):880–887. doi:10.1093/humrep/dei413 CrossRefPubMed

39.

Surve VV, Andersson N, Alatalo S, Lehto-Axtelius D, Halleen J, Vaananen K, Hakanson R (2001) Does combined gastrectomy and ovariectomy induce greater osteopenia in young female rats than gastrectomy alone? Calcif Tissue Int 69(5):274–280CrossRefPubMed

40.

Xie L, Rubin C, Judex S (2008) Enhancement of the adolescent murine musculoskeletal system using low-level mechanical vibrations. J Appl Physiol (1985) 104(4):1056–1062. doi:10.1152/japplphysiol.00764.2007 CrossRef

41.

Jee WS, Yao W (2001) Overview: animal models of osteopenia and osteoporosis. J Musculoskelet Neuronal Interact 1(3):193–207PubMed

42.

Giangregorio L, McCartney N (2006) Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies. J Spinal Cord Med 29(5):489–500PubMedCentralPubMed

43.

Wallace I, Pagnotti G, Rubin-Sigler J, Naeher M, Judex S, Rubin CT, Demes B (2015) Focal enhancement of the skeleton to exercise correlates to Mesenchymal stem cell responsivity rather than peak forces. J Exp Biol

44.

Styner M, Thompson WR, Galior K, Uzer G, Wu X, Kadari S, Case N, Xie Z, Sen B, Romaine A, Pagnotti GM, Rubin CT, Styner MA, Horowitz MC, Rubin J (2014) Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone 64:39–46. doi:10.1016/j.bone.2014.03.044 PubMedCentralCrossRefPubMed

Title: Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals
Authors: D. Krishnamoorthy
D. M. Frechette
B. J. Adler
D. E. Green
M. E. Chan
C. T. Rubin
Publication date: 01-02-2016
Publisher: Springer London
Published in: Osteoporosis International / Issue 2/2016
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-015-3289-5

At a glance: The STEP trials

Springer Medicine

Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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