The Central Role of Osteocytes in the Four Adaptive Pathways of Bone's Mechanostat.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0375434 Publication Model: Print Cited Medium: Internet ISSN: 1538-3008 (Electronic) Linking ISSN: 00916331 NLM ISO Abbreviation: Exerc Sport Sci Rev Subsets: MEDLINE

Publication: 2000- : Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: New York, Academic Press.

Bone Regeneration* ; Bone Resorption*; Osteocytes/*physiology; Adaptation, Physiological ; Animals ; Biomechanical Phenomena ; Cortical Bone/physiology ; Humans ; Stress, Mechanical ; Weight-Bearing/physiology

We review evidence supporting an updated mechanostat model in bone that highlights the central role of osteocytes within bone's four mechanoadaptive pathways: 1) formation modeling and 2) targeted remodeling, which occur with heightened mechanical loading, 3) resorption modeling, and 4) disuse-mediated remodeling, which occur with disuse. These four pathways regulate whole-bone stiffness in response to changing mechanical demands.

Frost HM. The Utah Paradigm of Skeletal Physiology. Greece: International Society of Musculoskeletal and Nueronal Interactions; 2004. 444 p.
Martin RB. The importance of mechanical loading in bone biology and medicine. J. Musculoskelet Neuronal Interact. 2007; 7(1):48–53.
Warden SJ, Hurst JA, Sanders MS, Turner CH, Burr DB, Li J. Bone adaptation to a mechanical loading program significantly increases skeletal fatigue resistance. J. Bone Miner Res. 2005; 20(5):809–16.
Robling AG, Hinant FM, Burr DB, Turner CH. Improved bone structure and strength after long-term mechanical loading is greatest if loading is separated into short bouts. J. Bone Miner Res. 2002; 17(8):1545–54.
Uthoff HK, Jaworski ZF. Bone loss in response to long-term immobilisation. J. Bone Joint Surg Br. 1978; 60B:420–9.
Ellman R, Spatz J, Cloutier A, Palme R, Christiansen BA, Bouxsein ML. Partial reductions in mechanical loading yield proportional changes in bone density, bone architecture, and muscle mass. J. Bone Miner Res. 2013; 28(4):875–85.
Burkhart K, Allaire B, Anderson DE, Lee D, Keaveny TM, Bouxsein ML. Effects of long-duration spaceflight on vertebral strength and risk of spine fracture. J. Bone Miner Res. 2019; 35:269–76.
Bouxsein ML, Seeman E. Quantifying the material and structural determinants of bone strength. Best Pract. Res. Clin. Rheumatol. 2009; 23(6):741–53.
Currey JD. Bones: Structure and Mechanics. Princeton: Princeton University Press; 2002.
Skerry TM. One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture. J. Musculoskelet. Neuronal Interact. 2006; 6(2):122–7.
Parfitt AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone. 2002; 30(1):5–7.
Fuchs RK, Allen MR, Ruppel ME, et al. In situ examination of the time-course for secondary mineralization of Haversian bone using synchrotron Fourier transform infrared microspectroscopy. Matrix Biol. 2008; 27(1):34–41.
Heaney RP. The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change. J. Bone Miner Res. 1994; 9(10):1515–23.
Seeman E. Bone modeling and remodeling. Crit. Rev. Eukaryot. Gene Expr. 2009; 19(3):219–33.
Szulc P, Seeman E. Thinking inside and outside the envelopes of bone: dedicated to PDD. Osteoporos Int. 2009; 20(8):1281–8.
Jepsen KJ. Functional interactions among morphologic and tissue quality traits define bone quality. Clin. Orthop. Relat. Res. 2011; 469(8):2150–9.
Schaffler MB, Cheung WY, Majeska R, Kennedy O. Osteocytes: master orchestrators of bone. Calcif. Tissue Int. 2014; 94(1):5–24.
Uda Y, Azab E, Sun N, Shi C, Pajevic PD. Osteocyte mechanobiology. Curr. Osteoporos. Rep. 2017; 15(4):318–25.
Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading–induced bone fluid shear stresses. J. Biomech. 1994; 27(3):339–60.
Wang Y, McNamara LM, Schaffler MB, Weinbaum S. Strain amplification and integrin based signaling in osteocytes. J. Musculoskelet Neuronal Interact. 2008; 8(4):332–4.
Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ. Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J. Cell. Physiol. 2007; 212(1):207–14.
Pathak JL, Bravenboer N, Luyten FP, et al. Mechanical loading reduces inflammation-induced human osteocyte-to-osteoclast communication. Calcif. Tissue Int. 2015; 97(2):169–78.
Metzger CE, Brezicha JE, Elizondo JP, Narayanan SA, Hogan HA, Bloomfield SA. Differential responses of mechanosensitive osteocyte proteins in fore- and hindlimbs of hindlimb-unloaded rats. Bone. 2017; 105:26–34.
Brady RT, O'Brien FJ, Hoey DA. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation. Biochem Biophys Res Commun. 2015; 459(1):118–23.
Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 2008; 283(9):5866–75.
Barak MM. Bone modeling or bone remodeling: that is the question. Am. J. Phys. Anthropol. 2019. Epub 2019/11/12. doi: 10.1002/ajpa.23966. PubMed PMID: 31710704. (PMID: 10.1002/ajpa.23966.)
Birkhold AI, Razi H, Duda GN, Weinkamer R, Checa S, Willie BM. The influence of age on adaptive bone formation and bone resorption. Biomaterials. 2014; 35(34):9290–301.
Hughes JM, Gaffney-Stomberg E, Guerriere KI, et al. Changes in tibial bone microarchitecture in female recruits in response to 8 weeks of U.S. Army Basic Combat Training. Bone. 2018; 113:9–16.
Seref-Ferlengez Z, Kennedy OD, Schaffler MB. Bone microdamage, remodeling and bone fragility: how much damage is too much damage? Bonekey Rep. 2015; 4:644.
Kennedy OD, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo. Bone. 2014; 64:132–7.
Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J. Bone Miner Res. 2000; 15(1):60–7.
Bentolila V, Boyce TM, Fyhrie DP, Drumb R, Skerry TM, Schaffler MB. Intracortical remodeling in adult rat long bones after fatigue loading. Bone. 1998; 23(3):275–81.
Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Miner Res. 2009; 24(4):597–605.
Taylor D, Kuiper JH. The prediction of stress fractures using a ‘stressed volume’ concept. J. Orthop. Res. 2001; 19(5):919–26.
Gross TS, Rubin CT. Uniformity of resorptive bone loss induced by disuse. J. Orthop. Res. 1995; 13(5):708–14.
Jaworski ZF, Uhthoff HK. Reversibility of nontraumatic disuse osteoporosis during its active phase. Bone. 1986; 7(6):431–9.
Cabahug-Zuckerman P, Frikha-Benayed D, Majeska RJ, et al. Osteocyte apoptosis caused by hindlimb unloading is required to trigger osteocyte RANKL production and subsequent resorption of cortical and trabecular bone in mice femurs. J. Bone Miner Res. 2016; 31:1356–65.
Plotkin LI, Gortazar AR, Davis HM, et al. Inhibition of osteocyte apoptosis prevents the increase in osteocytic receptor activator of nuclear factor kappaB ligand (RANKL) but does not stop bone resorption or the loss of bone induced by unloading. J. Biol. Chem. 2015; 290(31):18934–42.
Aguirre JI, Plotkin LI, Stewart SA, et al. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J. Bone Miner Res. 2006; 21(4):605–15.
Tatsumi S, Ishii K, Amizuka N, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007; 5(6):464–75.
Sugiyama T, Meakin LB, Browne WJ, Galea GL, Price JS, Lanyon LE. Bones' adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. J. Bone Miner Res. 2012; 27(8):1784–93.
Alexandre C, Vico L. Pathophysiology of bone loss in disuse osteoporosis. Joint Bone Spine. 2011; 78(6):572–6.
Ausk BJ, Huber P, Poliachik SL, Bain SD, Srinivasan S, Gross TS. Cortical bone resorption following muscle paralysis is spatially heterogeneous. Bone. 2012; 50(1):14–22.
Thomas T, Vico L, Skerry TM, et al. Architectural modifications and cellular response during disuse-related bone loss in calcaneus of the sheep. J. Appl. Physiol. 1996; 80(1):198–202.
Hughes JM, Popp KL, Yanovich R, Bouxsein ML, Matheny RW Jr. The role of adaptive bone formation in the etiology of stress fracture. Exp. Biol. Med. (Maywood). 2017; 242(9):897–906.
Hughes JM, Smith MA, Henning PC, et al. Bone formation is suppressed with multi-stressor military training. Eur. J. Appl. Physiol. 2014; 114(11):2251–9.
Hughes JM, McKinnon CJ, Taylor KM, et al. Nonsteroidal anti-inflammatory drug prescriptions are associated with increased stress fracture diagnosis in the US Army population. J. Bone Miner Res. 2019; 34(3):429–36.
Kim H, Wrann CD, Jedrychowski M, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell. 2019; 178(2):507–8.
Storlino G, Colaianni G, Sanesi L, et al. Irisin prevents disuse-induced osteocyte apoptosis. J. Bone Miner Res. 2019; 35:766–75.
Bach-Gansmo FL, Wittig NK, Bruel A, Thomsen JS, Birkedal H. Immobilization and long-term recovery results in large changes in bone structure and strength but no corresponding alterations of osteocyte lacunar properties. Bone. 2016; 91:139–47.
Kohrt WM, Wherry SJ, Wolfe P, et al. Maintenance of serum ionized calcium during exercise attenuates parathyroid hormone and bone resorption responses. J. Bone Miner Res. 2018; 33(7):1326–34.

Date Created: 20200623 Date Completed: 20201026 Latest Revision: 20210119

20221213

PMC7310270

10.1249/JES.0000000000000225

32568926