Mechanical loading and bone formation

Mechanical loading provides an anabolic stimulus for bone. More importantly, the mechanosensing apparatus in bone directs osteogenesis to where it is most needed for improving bone strength. The biological processes involved in bone mechanotransduction are poorly understood, and further investigation of the molecular mechanisms involved might uncover drug targets for osteoporosis. Several pathways are emerging from current research, including membrane ion channels, adenosine triphosphate (ATP) signaling, and second messengers, such as prostaglandins and nitric oxide. Some key molecular targets include the alpha 1C isoform of the L-type calcium channel, a gadolinium-sensitive stretch-activated channel, P2Y2 and P2X7 purinergic receptors, EP2 and EP4 prostanoid receptors, and the parathyroid hormone receptor.

[1]  K. Burridge,et al.  Disruption of the actin cytoskeleton after microinjection of proteolytic fragments of alpha-actinin , 1991, The Journal of cell biology.

[2]  J. Frangos,et al.  Fluid shear stress as a mediator of osteoblast cyclic adenosine monophosphate production , 1990, Journal of cellular physiology.

[3]  M. Forwood,et al.  Inducible cyclo‐oxygenase (COX‐2) mediates the induction of bone formation by mechanical loading in vivo , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  T. Steinberg,et al.  Regulation of connexin43 expression and function by prostaglandin E2 (PGE2) and parathyroid hormone (PTH) in osteoblastic cells , 1998 .

[5]  S. Keila,et al.  Systemic prostaglandin E2 increases cancellous bone formation and mass in aging rats and stimulates their bone marrow osteogenic capacity in vivo and in vitro. , 2001, The Journal of endocrinology.

[6]  R L Duncan,et al.  Ca(2+) regulates fluid shear-induced cytoskeletal reorganization and gene expression in osteoblasts. , 2000, American journal of physiology. Cell physiology.

[7]  J. Chow,et al.  Role of Nitric Oxide and Prostaglandins in Mechanically Induced Bone Formation , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[8]  L. Lanyon,et al.  Involvement of different ion channels in osteoblasts' and osteocytes' early responses to mechanical strain. , 1996, Bone.

[9]  Bom-taeck Kim,et al.  The Structural and Hormonal Basis of Sex Differences in Peak Appendicular Bone Strength in Rats , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  J A Frangos,et al.  Fluid flow stimulates rapid and continuous release of nitric oxide in osteoblasts. , 1996, The American journal of physiology.

[11]  P. Gallagher,et al.  Fluid shear stress inhibits TNF‐α‐induced apoptosis in osteoblasts: A role for fluid shear stress‐induced activation of PI3‐kinase and inhibition of caspase‐3 , 2003, Journal of cellular physiology.

[12]  H. Frost.  Bone's mechanostat: a 2003 update. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[13]  P. Kannus,et al.  Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading. , 2003, Bone.

[14]  H J Donahue,et al.  Osteopontin Gene Regulation by Oscillatory Fluid Flow via Intracellular Calcium Mobilization and Activation of Mitogen-activated Protein Kinase in MC3T3–E1 Osteoblasts* , 2001, The Journal of Biological Chemistry.

[15]  C. Ackert-Bicknell,et al.  Nitric oxide regulates receptor activator of nuclear factor-kappaB ligand and osteoprotegerin expression in bone marrow stromal cells. , 2004, Endocrinology.

[16]  G. Murrell,et al.  Nitric oxide inhibitor L-NAME suppresses mechanically induced bone formation in rats. , 1996, The American journal of physiology.

[17]  Wei Wei,et al.  Parathyroid Hormone and Mechanical Usage Have a Synergistic Effect in Rat Tibial Diaphyseal Cortical Bone , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  J. Gustafsson,et al.  Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. , 1999, The Journal of clinical investigation.

[19]  J. Gustafsson,et al.  Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio and serum interleukin-6 in male mice. , 2001, The Journal of endocrinology.

[20]  Christopher R Jacobs,et al.  P2Y Purinoceptors Are Responsible for Oscillatory Fluid Flow-induced Intracellular Calcium Mobilization in Osteoblastic Cells* , 2002, The Journal of Biological Chemistry.

[21]  C. Leu,et al.  Prostaglandin receptor EP(4) mediates the bone anabolic effects of PGE(2). , 2001, Molecular pharmacology.

[22]  G. Frankel,et al.  Metallurgy (communication arising): Stainless-steel corrosion and MnS inclusions , 2003, Nature.

[23]  S. M. Sims,et al.  Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. , 2003, Molecular endocrinology.

[24]  N. Lane,et al.  Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis , 2003, Osteoporosis International.

[25]  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.

[26]  R. Duncan,et al.  Parathyroid Hormone Enhances Fluid Shear‐Induced [Ca2+]i Signaling in Osteoblastic Cells Through Activation of Mechanosensitive and Voltage‐Sensitive Ca2+ Channels , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  C. Turner,et al.  Three-dimensional Modeling of the Effects of Parathyroid Hormone on Bone Distribution in Lumbar Vertebrae of Ovariectomized Cynomolgus Macaques , 2000, Osteoporosis International.

[28]  Jiliang Li,et al.  Parathyroid hormone enhances mechanically induced bone formation, possibly involving L-type voltage-sensitive calcium channels. , 2003, Endocrinology.

[29]  J. Chow,et al.  Role for parathyroid hormone in mechanical responsiveness of rat bone. , 1998, American journal of physiology. Endocrinology and metabolism.

[30]  S. Weinbaum,et al.  A new view of mechanotransduction and strain amplification in cells with microvilli and cell processes. , 2001, Biorheology.

[31]  T. Kasten,et al.  Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Hung,et al.  Intracellular Ca2+ stores and extracellular Ca2+ are required in the real-time Ca2+ response of bone cells experiencing fluid flow. , 1996, Journal of biomechanics.

[33]  M. Gray,et al.  Osteoblast cytoskeletal modulation in response to mechanical strain in vitro , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[34]  Elisabeth H Burger,et al.  Interactive effects of PTH and mechanical stress on nitric oxide and PGE2 production by primary mouse osteoblastic cells. , 2003, American journal of physiology. Endocrinology and metabolism.

[35]  W. Jee,et al.  Transient effects of subcutaneously administered prostaglandin E2 on cancellous and cortical bone in young adult dogs. , 1990, Bone.

[36]  L. Lanyon,et al.  Mechanical Strain and Estrogen Activate Estrogen Receptor α in Bone Cells , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[37]  S. Mohan,et al.  Two Different Pathways for the Maintenance of Trabecular Bone in Adult Male Mice , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  L. Bonewald,et al.  PGE2 Is Essential for Gap Junction-Mediated Intercellular Communication between Osteocyte-Like MLO-Y4 Cells in Response to Mechanical Strain. , 2001, Endocrinology.

[39]  J A Frangos,et al.  Activation of G proteins mediates flow-induced prostaglandin E2 production in osteoblasts. , 1997, Endocrinology.

[40]  P. Nibbering,et al.  Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption. , 1994, The Journal of clinical investigation.

[41]  D. Burr,et al.  Fluid shear-induced mechanical signaling in MC3T3-E1 osteoblasts requires cytoskeleton-integrin interactions. , 1998, American journal of physiology. Cell physiology.

[42]  K. Chihara,et al.  Parathyroid Hormone-activated Volume-sensitive Calcium Influx Pathways in Mechanically Loaded Osteocytes* , 2000, The Journal of Biological Chemistry.

[43]  L. Lanyon,et al.  Mechanical strain activates estrogen response elements in bone cells. , 2000, Bone.

[44]  E H Burger,et al.  Pulsating Fluid Flow Stimulates Prostaglandin Release and Inducible Prostaglandin G/H Synthase mRNA Expression in Primary Mouse Bone Cells , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  D. B. Burr,et al.  Suppression of Prostaglandin Synthesis with NS-398 Has Different Effects on Endocortical and Periosteal Bone Formation Induced by Mechanical Loading , 2002, Calcified Tissue International.

[46]  T. Steinberg,et al.  ATP- and Gap Junction–dependent Intercellular Calcium Signaling in Osteoblastic Cells , 1997, The Journal of cell biology.

[47]  R. Turner,et al.  Estrogen inhibition of periosteal bone formation in rat long bones: down-regulation of gene expression for bone matrix proteins. , 1990, Endocrinology.

[48]  Cheryl L. Ackert-Bicknell,et al.  Nitric Oxide Regulates Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin Expression in Bone Marrow Stromal Cells , 2004 .

[49]  L. Bonewald,et al.  PGE(2) is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. , 2001, Endocrinology.

[50]  G. Rodan,et al.  Cyclic AMP and cyclic GMP: mediators of the mechanical effects on bone remodeling. , 1975, Science.

[51]  S. Narumiya,et al.  Prostaglandin E2 (PGE2) Autoamplifies its Production Through EP1 Subtype of PGE Receptor in Mouse Osteoblastic MC3T3-E1 Cells , 1998, Calcified Tissue International.

[52]  Jiliang Li,et al.  L‐Type Calcium Channels Mediate Mechanically Induced Bone Formation In Vivo , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[53]  H. Datta,et al.  Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP. , 1991, Proceedings of the National Academy of Sciences of the United States of America.