Modeling of biological doses and mechanical effects on bone transduction.

Shear stress, hormones like parathyroid and mineral elements like calcium mediate the amplitude of stimulus signal, which affects the rate of bone remodeling. The current study investigates the theoretical effects of different metabolic doses in stimulus signal level on bone. The model was built considering the osteocyte as the sensing center mediated by coupled mechanical shear stress and some biological factors. The proposed enhanced model was developed based on previously published works dealing with different aspects of bone transduction. It describes the effects of physiological doses variations of calcium, parathyroid hormone, nitric oxide and prostaglandin E2 on the stimulus level sensed by osteocytes in response to applied shear stress generated by interstitial fluid flow. We retained the metabolic factors (parathyroid hormone, nitric oxide and prostaglandin E2) as parameters of bone cell mechanosensitivity because stimulation/inhibition of induced pathways stimulates osteogenic response in vivo. We then tested the model response in terms of stimulus signal variation versus the biological factors doses to external mechanical stimuli. Despite the limitations of the model, it is consistent and has physiological bases. Biological inputs are histologically measurable. This makes the model amenable to experimental verification.

[1]  Margaret Warner,et al.  Estrogen receptors: how do they signal and what are their targets. , 2007, Physiological reviews.

[2]  C. Fullmer,et al.  Vitamin D and intestinal calcium transport: facts, speculations and hypotheses. , 1995, The Journal of nutrition.

[3]  Anna Teti,et al.  Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. , 2009, Bone.

[4]  Ridha Hambli,et al.  Multiscale methodology for bone remodelling simulation using coupled finite element and neural network computation , 2011, Biomechanics and modeling in mechanobiology.

[5]  Matthew M Riggs,et al.  A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. , 2010, Bone.

[6]  T. Adachi,et al.  Trabecular bone remodelling simulation considering osteocytic response to fluid-induced shear stress , 2010, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[7]  W. Willett,et al.  Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women. , 2003, The American journal of clinical nutrition.

[8]  J. Klein-Nulend,et al.  MECHANOTRANSDUCTION IN BONE : ROLE OF THE LACUNOCANALICULAR NETWORK , 1999 .

[9]  Shelley Hurwitz,et al.  The effects of age and gender on parathyroid hormone dynamics , 2000, Clinical endocrinology.

[10]  C S Brazel,et al.  Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent drug release from relaxing structures. , 1999, Biomaterials.

[11]  A. Pitsillides,et al.  Mechanical strain‐induced NO production by bone cells: a possible role in adaptive bone (re)modeling? , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  Svetlana V Komarova,et al.  Mathematical model predicts a critical role for osteoclast autocrine regulation in the control of bone remodeling. , 2003, Bone.

[13]  Vincent Lemaire,et al.  Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. , 2004, Journal of theoretical biology.

[14]  W S S Jee,et al.  The benefit of combining non-mechanical agents with mechanical loading: a perspective based on the Utah Paradigm of Skeletal Physiology. , 2005, Journal of musculoskeletal & neuronal interactions.

[15]  The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone diseases. II. PTH and bone cells: bone turnover and plasma calcium regulation. , 1976, Metabolism: clinical and experimental.

[16]  J M Polak,et al.  Bidirectional regulation of osteoclast function by nitric oxide synthase isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  S. Weinbaum,et al.  A model for the role of integrins in flow induced mechanotransduction in osteocytes , 2007, Proceedings of the National Academy of Sciences.

[18]  R. A. Brand,et al.  Modeling Deformation-Induced Fluid Flow in Cortical Bone’s Canalicular–Lacunar System , 2005, Annals of Biomedical Engineering.

[19]  M. Rashid,et al.  A mechanistic model for internal bone remodeling exhibits different dynamic responses in disuse and overload. , 2001, Journal of biomechanics.

[20]  N. Koszewski,et al.  Parathyroid Hormone/Parathyroid Hormone‐Related Peptide Type 1 Receptor in Human Bone , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  Nilima Nigam,et al.  Mathematical Modeling of Spatio‐Temporal Dynamics of a Single Bone Multicellular Unit , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  E H Burger,et al.  The production of nitric oxide and prostaglandin E(2) by primary bone cells is shear stress dependent. , 2001, Journal of biomechanics.

[23]  Jenneke Klein-Nulend,et al.  A comparison of strain and fluid shear stress in stimulating bone cell responses—a computational and experimental study , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  L. Greller,et al.  Response to continuous and pulsatile PTH dosing: a mathematical model for parathyroid hormone receptor kinetics. , 2005, Bone.

[25]  M G Mullender,et al.  Mechanobiology of bone tissue. , 2005, Pathologie-biologie.

[26]  Stephen C. Cowin,et al.  Mechanotransduction and flow across the endothelial glycocalyx , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  F. Allgöwer,et al.  Mathematical Modeling and Analysis of Force Induced Bone Growth , 2006, 2006 International Conference of the IEEE Engineering in Medicine and Biology Society.

[28]  Ridha Hambli,et al.  Strain–damage coupled algorithm for cancellous bone mechano-regulation with spatial function influence , 2009 .

[29]  D. Goltzman,et al.  Interactions of PTH and PTHrP with the PTH/PTHrP Receptor and with Downstream Signaling Pathways: Exceptions That Provide the Rules , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  S. Cowin,et al.  A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. , 1994, Journal of biomechanics.

[31]  L. Raisz,et al.  Prostaglandins and bone metabolism , 2020, Principles of Bone Biology.

[32]  Salah Naili,et al.  Transverse isotropic poroelastic osteon model under cyclic loading , 2005 .

[33]  R A Brand,et al.  Micromechanically based poroelastic modeling of fluid flow in Haversian bone. , 2003, Journal of biomechanical engineering.

[34]  L. Bonewald,et al.  Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. , 2007, Journal of biomechanics.

[35]  D. Kalu,et al.  Strain differences in bone density and calcium metabolism between C3H/HeJ and C57BL/6J mice. , 1999, Bone.

[36]  P. Houillier.  Le récepteur du calcium : un rôle central dans le métabolisme calcique , 2009 .

[37]  Sheldon Weinbaum,et al.  Mechanotransduction and strain amplification in osteocyte cell processes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  P J Prendergast,et al.  Microdamage and osteocyte-lacuna strain in bone: a microstructural finite element analysis. , 1996, Journal of biomechanical engineering.

[39]  Donald L. Cooper,et al.  Influence of cortical canal architecture on lacunocanalicular pore pressure and fluid flow , 2008, Computer methods in biomechanics and biomedical engineering.

[40]  Patrick J Prendergast,et al.  Bone remodelling algorithms incorporating both strain and microdamage stimuli. , 2007, Journal of biomechanics.

[41]  R. St-Arnaud.  The direct role of vitamin D on bone homeostasis. , 2008, Archives of biochemistry and biophysics.

[42]  J. Bilezikian,et al.  The cell biology of parathyroid hormone in osteoblasts , 2008, Current osteoporosis reports.

[43]  Svetlana V Komarova,et al.  Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. , 2005, Endocrinology.

[44]  Mark L. Johnson,et al.  Osteocytes, mechanosensing and Wnt signaling. , 2008, Bone.

[45]  John P. Bilezikian,et al.  Principles of Bone Biology , 1996 .

[46]  Thibault Lemaire,et al.  Multiscale analysis of the coupled effects governing the movement of interstitial fluid in cortical bone , 2006, Biomechanics and modeling in mechanobiology.