IU Indianapolis ScholarWorks :: Browsing by Subject "bone"

Browsing by Subject "bone"

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Anatomy and physiology of the mineralized tissues: Role in the pathogenesis of osteoarthrosis
(2004) Burr, David B.
Synovial joints are composed of several different kinds of tissue that interact to protect normal joint function. Three subchondral mineralized tissues can be identified – calcified cartilage, subchondral cortical bone, and subchondral trabecular bone – which are distinguished morphologically, physiologically, and mechanically. Each responds to mechanical and pharmaceutical stimuli in different ways through processes of growth, modeling, and remodeling, and changes in each may have a distinct effect on the health of the joint. It is important to distinguish between the structural properties of these tissues and their material properties as these change differently in osteoarthrosis (OA). It is likely that changes in the mineral content and thickness of the calcified cartilage play a greater role in the pathogenesis of OA than has been realized, whereas changes in trabecular bone are probably not causative. Changes in the subchondral cortical bone may accelerate progression of pre-existing disease, but the combined effects of increased subchondral bone turnover and greater subchondral bone volume are not at all clear. Ultimately, the efficacy of bone anti-resorptive therapies for OA will depend upon whether the increased structural stiffness of the subchondral mineralized tissues predisposes the cartilage to deteriorate, whether the increased bone turnover that occurs in OA is itself a causative factor, or whether the lower tissue elastic modulus offsets the increased structural stiffness of the subchondral plate in an attempt to protect the cartilage from damage.
Chapter Six - Molecular signaling in bone cells: Regulation of cell differentiation and survival
(Elsevier, 2019-02-04) Plotkin, Lilian I.; Bruzzaniti, Angela; Biomedical Sciences and Comprehensive Care, School of Dentistry
The achievement of proper bone mass and architecture, and their maintenance throughout life requires the concerted actions of osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells. The differentiation and activity of osteoblasts and osteoclasts are regulated by molecules produced by matrix-embedded osteocytes, as well as by cross-talk between osteoblasts and osteoclasts through secreted factors. In addition, it is likely that direct contact between osteoblast and osteoclast precursors, and the contact of these cells with osteocytes and cells in the bone marrow, also modulate bone cell differentiation and function. With the advancement of molecular and genetic tools, our comprehension of the intracellular signals activated in bone cells has evolved significantly, from early suggestions that osteoblasts and osteoclasts have common precursors and that osteocytes are inert cells in the bone matrix, to the very sophisticated understanding of a network of receptors, ligands, intracellular kinases/phosphatases, transcription factors, and cell-specific genes that are known today. These advances have allowed the design and FDA-approval of new therapies to preserve and increase bone mass and strength in a wide variety of pathological conditions, improving bone health from early childhood to the elderly. We have summarized here the current knowledge on selected intracellular signal pathways activated in osteoblasts, osteocytes, and osteoclasts.
Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis
(2005-09-27) Miura, Yasuo; Miura, Masako; Gronthos, Stan; Allen, Matthew R.; Cao, Chunzhang; Uveges, Thomas E.; Bi, Yanming; Ehirchiou, Driss; Kortesidis, Angela; Shi, Songtao; Zhang, Li
Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis.
The Effects of High Fat Diet, Bone Healing, and BMP-2 Treatment on Endothelial Cell Growth and Function
(Elsevier, 2021-05) Bhatti, Fazal Ur Rehman; Dadwal, Ushashi C.; Valuch, Conner R.; Tewari, Nikhil P.; Awosanya, Olatundun D.; Staut, Caio de Andrade; Sun, Seungyup; Mendenhall, Stephen K.; Perugini, Anthony J., III; Nagaraj, Rohit U.; Battini, Hanisha L.; Nazzal, Murad K.; Blosser, Rachel J.; Maupin, Kevin A.; Childress, Paul J.; Li, Jiliang; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
Angiogenesis is a vital process during the regeneration of bone tissue. The aim of this study was to investigate angiogenesis at the fracture site as well as at distal locations from obesity-induced type 2 diabetic mice that were treated with bone morphogenetic protein-2 (BMP-2, local administration at the time of surgery) to heal a femoral critical sized defect (CSD) or saline as a control. Mice were fed a high fat diet (HFD) to induce a type 2 diabetic-like phenotype while low fat diet (LFD) animals served as controls. Endothelial cells (ECs) were isolated from the lungs (LECs) and bone marrow (BMECs) 3 weeks post-surgery, and the fractured femurs were also examined. Our studies demonstrate that local administration of BMP-2 at the fracture site in a CSD model results in complete bone healing within 3 weeks for all HFD mice and 66.7% of LFD mice, whereas those treated with saline remain unhealed. At the fracture site, vessel parameters and adipocyte numbers were significantly increased in BMP-2 treated femurs, irrespective of diet. At distal sites, LEC and BMEC proliferation was not altered by diet or BMP-2 treatment. HFD increased the tube formation ability of both LECs and BMECs. Interestingly, BMP-2 treatment at the time of surgery reduced tube formation in LECs and humeri BMECs. However, migration of BMECs from HFD mice treated with BMP-2 was increased compared to BMECs from HFD mice treated with saline. BMP-2 treatment significantly increased the expression of CD31, FLT-1, and ANGPT2 in LECs and BMECs in LFD mice, but reduced the expression of these same genes in HFD mice. To date, this is the first study that depicts the systemic influence of fracture surgery and local BMP-2 treatment on the proliferation and angiogenic potential of ECs derived from the bone marrow and lungs.
Improved autologous cortical bone harvest and viability with 2Flute otologic burs
(Wiley, 2018-01) Roth, Adam A.; Tang, Pei-Ciao; Ye, Michael J.; Mohammad, Khalid S.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of Medicine
Objectives To determine if 2Flute (Stryker Corporation, Kalamazoo, MI) otologic burs improve the size, cellular content, and bone healing of autologous cortical bone grafts harvested during canal wall reconstruction (CWR) tympanomastoidectomy with mastoid obliteration. Study Design Institutional review board-approved prospective cohort study. Methods Human autologous cortical bone chips were harvested using various burs (4 and 6 mm diameter; multiflute, and 2Flute [Stryker Corporation]) from patients undergoing CWR tympanomastoidectomy for the treatment of chronic otitis media with cholesteatoma. Bone chip size, cell counts, cellular gene expression, and new bone formation were quantified. Results Bone chips were significantly larger when harvested with 2Flute (Stryker Corporation) bur compared to multiflute burs at both 6 mm diameter (113 ± 14 μm2 vs. 66 ± 8 μm2; P < 0.05) and 4 mm diameter (70 ± 8 μm2 vs. 50 ± 3 μm2; P < 0.05). After 2 weeks in culture, cell numbers were significantly higher when harvested with 2Flute (Stryker Corporation) bur compared to multiflute burs at both 6 mm diameter (48.7 ± 3 vs. 31.8 ± 3 cells/μg bone; P < 0.05) and 4 mm diameter (27.6 ± 1.2 vs. 8.8 ± 1.2 cells/μg bone; P < 0.05). Bone-derived cells express osteoblast markers (alkaline phosphatase, osteocalcin). Cultured cells are able to form new bone in culture, and bone formation is facilitated by the presence of bone chips. Conclusion Use of 2Flute (Stryker Corporation) otologic burs for human autologous cortical bone harvest results in more viable bone fragments, with larger bone chips and more osteoblasts. Future studies are needed to determine if this leads to improved bone healing.
In vivo axial loading of the mouse tibia
(Springer, 2015) Melville, Katherine M.; Robling, Alexander G.; van der Meulen, Marjolein C. H.; Department of Anatomy and Cell Biology, IU School of Medicine
Noninvasive methods to apply controlled, cyclic loads to the living skeleton are used as anabolic procedures to stimulate new bone formation in adults and enhance bone mass accrual in growing animals. These methods are also invaluable for understanding bone signaling pathways. Our focus here is on a particular loading model: in vivo axial compression of the mouse tibia. An advantage of loading the tibia is that changes are present in both the cancellous envelope of the proximal tibia and the cortical bone of the tibial diaphysis. To load the tibia of the mouse axially in vivo, a cyclic compressive load is applied up to five times a week to a single tibia per mouse for a duration lasting from 1 day to 6 weeks. With the contralateral limb as an internal control, the anabolic response of the skeleton to mechanical stimuli can be studied in a pairwise experimental design. Here, we describe the key parameters that must be considered before beginning an in vivo mouse tibial loading experiment, including methods for in vivo strain gauging of the tibial midshaft, and then we describe general methods for loading the mouse tibia for an experiment lasting multiple days.
Influence of Mechanical Stimulation on the Quantity and Quality of Bone During Modeling
(2016) Berman, Alycia G.; Wallace, Joseph; Na, Sungsoo; Li, Jiliang; Yoshida, Ken
Skeletal fractures due to bone disease impact an estimated 1.5 million Americans per year, creating a large economic burden on our society. Treatment of bone diseases prior to fracture often involves bisphosphonates (current gold-standard in osteoporosis care and prevention). Although bisphosphonates decrease fracture incidence, they often improve bone mass without regard for bone quality. Thus, although bisphosphonates increase the amount of bone present, the inherent bone material strength often decreases, creating a trade-off that increases the risk of atypical fractures after long-term use. This trade-off demonstrates the need for a treatment that targets both bone quality AND quantity. Although bone quality is important, the components of bone that contribute to bone quality are incompletely understood, making it difficult to create new pharmacological agents. With this in mind, my particular area of interest is in understanding how mechanical stimuli protects the formation of bone, leading to improved bone quality. Initially, this area was explored through use of tibial loading in a disease mouse model (osteolathyrism, induced by injection of beta-aminoproprionitrile) as a means of assessing how the body is able to compensate for decreased bone quality. The results of the BAPN and tibial loading studies indicated that injecting mice with BAPN may not be the ideal method to induce osteolathyrism. However, other intriguing results from the BAPN studies then led us into an exploration of how tibial loading itself contributes to bone quality.
Loss of the nutrient sensor TAS1R3 leads to reduced bone resorption
(Springer, 2018-02) Eaton, Michael S.; Weinstein, Nicholas; Newby, Jordan B.; Plattes, Maggie M.; Foster, Hanna E.; Arthur, Jon W.; Ward, Taylor D.; Shively, Stephen R.; Shor, Ryann; Nathan, Justin; Davis, Hannah M.; Plotkin, Lilian I.; Wauson, Eric M.; Dewar, Brian J.; Broege, Aaron; Lowery, Jonathan W.; Anatomy and Cell Biology, School of Medicine
The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling.
Mechanotransduction in Living Bone: Effects of the Keap1-Nrf2 Pathway
(2019-08) Priddy, Carlie; Li, Jiliang; Dai, Guoli; Wallace, Joseph M.
The Keap1-Nrf2 pathway regulates a wide range of cytoprotective genes, and has been found to serve a protective and beneficial role in many body systems. There is limited information available, however, about its role in bone homeostasis. While Nrf2 activation has been suggested as an effective method of increasing bone mass and quality, there have been conflicting reports which associate Keap1 deficiency with detrimental phenotypes. As Keap1 deletion is a common method of Nrf2 activation, further study should address the impacts of various methods of regulating Nrf2 expression. Also, little research has been conducted on the specific pathways by which Nrf2 activation improves bone quality. In this study, the effects of alterations to Nrf2 activation levels were explored in two specific and varied scenarios. In the first experiment, moderate Nrf2 activation was achieved via partial deletion of its sequestering protein, Keap1, in an aging mouse model. The hypothesis tested here is that moderate Nrf2 activation improves bone quality by affecting bone metabolism and response to mechanical loading. The results of this first experiment suggest a subtle, sex-specific effect of moderate Nrf2 activation in aging mice which improves specific indices of bone quality to varying degrees, but does not affect loading-induced bone formation. It is likely that the overwhelming phenotypic impacts associated with aging or the systemic effects of global Keap1 deficiency may increase the difficulty in parsing out significant effects that can be attributed solely to Nrf2 activation. In the second experiment, a cell-specific knockout of Nrf2 in the osteocytes was achieved using a Cre/Lox breeding system. The hypothesis tested here is that osteocyte-specific deletion of Nrf2 impairs bone quality by affecting bone metabolism and response to mechanical loading. The results of this experiment suggest an important role of Nrf2 in osteocyte function which improves certain indices of bone quality, which impacts male and female bones in different 7 ways, but did not significantly impact loading-induced bone formation. Further studies should modify the method of Nrf2 activation in an effort to refine the animal model, allowing the effects of Nrf2 to be isolated from the potential systemic effects of Keap1 deletion. Future studies should also utilize other conditional knockout models to elucidate the effects of Nrf2 in other specific cell types.
Megakaryocytes Regulate Expression of Pyk2 Isoforms and Caspase-mediated Cleavage of Actin in Osteoblasts
(2012-05) Kacena, Melissa A.; Eleniste, Pierre P.; Cheng, Ying-Hua; Huang, Su; Shivanna, Mahesh; Meijome, Tomas E.; Mayo, Lindsey D.; Bruzzaniti, Angela
The proliferation and differentiation of osteoblast (OB) precursors are essential for elaborating the bone-forming activity of mature OBs. However, the mechanisms regulating OB proliferation and function are largely unknown. We reported that OB proliferation is enhanced by megakaryocytes (MKs) via a process that is regulated in part by integrin signaling. The tyrosine kinase Pyk2 has been shown to regulate cell proliferation and survival in a variety of cells. Pyk2 is also activated by integrin signaling and regulates actin remodeling in bone-resorbing osteoclasts. In this study, we examined the role of Pyk2 and actin in the MK-mediated increase in OB proliferation. Calvarial OBs were cultured in the presence of MKs for various times, and Pyk2 signaling cascades in OBs were examined by Western blotting, subcellular fractionation, and microscopy. We found that MKs regulate the temporal expression of Pyk2 and its subcellular localization. We also found that MKs regulate the expression of two alternatively spliced isoforms of Pyk2 in OBs, which may regulate OB differentiation and proliferation. MKs also induced cytoskeletal reorganization in OBs, which was associated with the caspase-mediated cleavage of actin, an increase in focal adhesions, and the formation of apical membrane ruffles. Moreover, BrdU incorporation in MK-stimulated OBs was blocked by the actin-polymerizing agent, jasplakinolide. Collectively, our studies reveal that Pyk2 and actin play an important role in MK-regulated signaling cascades that control OB proliferation and may be important for therapeutic interventions aimed at increasing bone formation in metabolic diseases of the skeleton.

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