Bone Health in Patients with Multiple Sclerosis

Multiple sclerosis (MS) is a gait disorder characterized by acute episodes of neurological defects leading to progressive disability. Patients with MS have multiple risk factors for osteoporotic fractures, such as progressive immobilization, long-term glucocorticoids (GCs) treatment or vitamin D deficiency. The duration of motor disability appears to be a major contributor to the reduction of bone strength. The long term immobilization causes a marked imbalance between bone formation and resorption with depressed bone formation and a marked disruption of mechanosensory network of tightly connected osteocytes due to increase of osteocyte apoptosis. Patients with higher level of disability have also higher risk of falls that combined with a bone loss increases the frequency of bone fractures. There are currently no recommendations how to best prevent and treat osteoporosis in patients with MS. However, devastating effect of immobilization on the skeleton in patients with MS underscores the importance of adequate mechanical stimuli for maintaining the bone structure and its mechanical competence. The physical as well as pharmacological interventions which can counteract the bone remodeling imbalance, particularly osteocyte apoptosis, will be promising for prevention and treatment of osteoporosis in patients with MS.

Download Full-text

Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli

Journal of Endocrinology ◽

10.1677/joe-07-0119 ◽

2007 ◽

Vol 194 (1) ◽

pp. 213-222 ◽

Cited By ~ 26

Author(s):

Toshihiro Sugiyama ◽

Toshiaki Takaki ◽

Kenya Sakanaka ◽

Hiroki Sadamaru ◽

Koji Mori ◽

...

Keyword(s):

Computer Simulation ◽

Cortical Bone ◽

Bone Structure ◽

Biomechanical Properties ◽

Mechanical Stimuli ◽

Bone Material ◽

Material Quality ◽

Compensatory Adaptation ◽

Jumping Exercise

Long-term warfarin use has been reported to increase fracture risk of rib and vertebra but not hip in elderly patients, but the mechanisms remain unknown. We hypothesized that warfarin would impair bone material quality but could not weaken bone strength under conditions with higher mechanical stimuli. To test this hypothesis, rats were randomized to vehicle or warfarin group at 4 weeks of age and subsequently weight matched into a sedentary or jumping exercise group at 12 weeks of age. At 6 months of age, osteocalcin content, bone mineral density (BMD), mineral size, material properties, morphological parameters, and biomechanical properties of cortical bones were evaluated. In order to seek evidence for a common mechanism of action, effects of nucleation rate of mineral crystals on their rigidity were also investigated using computer simulation. In humeral cortical bones, warfarin did not change BMD, but markedly decreased osteocalcin content, diminished mineral size, and impaired material hardness. Consistent with these results, our computer-simulation model showed that osteocalcin-induced delay of mineral crystal nucleation decreased mineral formation rate, increased mean and distribution of mineral sizes, and strengthened mineral rigidity. In tibial cortical bones, warfarin decreased material ultimate stress; however, under jumping exercise, warfarin increased cross-sectional total and bone areas of these tibiae and completely maintained their biomechanical properties including work to failure. Collectively, our findings suggest that long-term warfarin therapy weakens rib and vertebra by impairing cortical bone material quality due to a marked decrease in osteocalcin content but could not reduce hip strength through compensatory adaptation of cortical bone structure to higher mechanical stimuli.

Download Full-text

Increased Potential of Bone Formation With Intravenous Injection of Parathyroid Hormone-minicircle DNA Vector

10.21203/rs.3.rs-88110/v1 ◽

2020 ◽

Author(s):

Jang-Woon Kim ◽

Narae Park ◽

Jaewoo Kang ◽

Yena Kim ◽

Hyerin Jung ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Bone Structure ◽

Therapeutic Potential ◽

Treatment Of Osteoporosis ◽

Intravenous Injections ◽

Parathyroid Hormone Related Protein ◽

Dna Vectors ◽

Minicircle Dna

Abstract Background: Osteoporosis is usually treated with long-term usage of anti-osteoporotic agents. However, poor drug compliance and emerging side effects sometimes are limitations for the treatment of osteoporosis. Parathyroid hormone-related protein (PTHrP) is needed for normal bone formation and remodeling. We attempted a new method using minicircle vectors (mc) encoding PTHrP analogs. Methods: We generated mc encoding the infusion of PTHrP 1-34 with 107-139 (mc 1-34+107-139). Ovariectomized (OVX) model was induced in 12-week-old C57BL/6 female mice. mc 1-34+107-139 was administered three times weekly via intravenous injections. Results: mc 1-34+107-139 significantly increased bone formation compared with the OVX group and decreased the bone resorption. PTHrP mc DNA vector was effective in increasing the quality of trabecular bone structure. Conclusions: These results provide experimental evidence for the therapeutic potential of minicircle DNA vectors in OVX model. This study is a first attempted proof-of-concept gene therapy using minicircle vectors for the treatment of osteoporosis.

Download Full-text

Increased Potential of Bone Formation with the Intravenous Injection of a Parathyroid Hormone-Related Protein Minicircle DNA Vector

International Journal of Molecular Sciences ◽

10.3390/ijms22169069 ◽

2021 ◽

Vol 22 (16) ◽

pp. 9069

Author(s):

Jang-Woon Kim ◽

Narae Park ◽

Jaewoo Kang ◽

Yena Kim ◽

Hyerin Jung ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Bone Structure ◽

Human Mesenchymal Stem Cells ◽

Treated Group ◽

Related Protein ◽

Parathyroid Hormone Related Protein ◽

Alternative Delivery ◽

Minicircle Dna

Osteoporosis is commonly treated via the long-term usage of anti-osteoporotic agents; however, poor drug compliance and undesirable side effects limit their treatment efficacy. The parathyroid hormone-related protein (PTHrP) is essential for normal bone formation and remodeling; thus, may be used as an anti-osteoporotic agent. Here, we developed a platform for the delivery of a single peptide composed of two regions of the PTHrP protein (1–34 and 107–139); mcPTHrP 1–34+107–139 using a minicircle vector. We also transfected mcPTHrP 1–34+107–139 into human mesenchymal stem cells (MSCs) and generated Thru 1–34+107–139-producing engineered MSCs (eMSCs) as an alternative delivery system. Osteoporosis was induced in 12-week-old C57BL/6 female mice via ovariectomy. The ovariectomized (OVX) mice were then treated with the two systems; (1) mcPTHrP 1–34+107–139 was intravenously administered three times (once per week); (2) eMSCs were intraperitoneally administered twice (on weeks four and six). Compared with the control OVX mice, the mcPTHrP 1–34+107–139-treated group showed better trabecular bone structure quality, increased bone formation, and decreased bone resorption. Similar results were observed in the eMSCs-treated OVX mice. Altogether, these results provide experimental evidence to support the potential of delivering PTHrP 1–34+107–139 using the minicircle technology for the treatment of osteoporosis.

Download Full-text

BONE ADAPTATION AND REGENERATION – NEW DEVELOPMENTS

International Journal of Modern Physics Conference Series ◽

10.1142/s201019451200791x ◽

2012 ◽

Vol 17 ◽

pp. 34-43 ◽

Cited By ~ 1

Author(s):

JENNEKE KLEIN-NULEND ◽

ROMMEL GAUD BACABAC

Keyword(s):

Bone Formation ◽

Cell Signaling ◽

Mechanical Loading ◽

Bone Structure ◽

Bone Cells ◽

Mechanical Energy ◽

Bone Adaptation ◽

Mechanical Stimuli ◽

Waste Products ◽

Local Bone

Bone is a dynamic tissue that is constantly renewed and adapts to its local loading environment. Mechanical loading results in adaptive changes in bone size and shape that strengthen bone structure. The mechanisms for adaptation involve a multistep process called mechanotransduction, which is the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells. The transduction of a mechanical signal to a biochemical response involves pathways within the cell membrane and cytoskeleton of the osteocytes, the professional mechansensor cells of bone. During the last decade the role of mechanosensitive osteocytes in bone metabolism and turnover, and the lacuno-canalicular porosity as the structure that mediates mechanosensing, is likely to reveal a new paradigm for understanding the bone formation response to mechanical loading, and the bone resorption response to disuse. Strain-derived fluid flow of interstitial fluid through the lacuno-canalicular porosity seems to mechanically activate the osteocytes, as well as ensures transport of cell signaling molecules, nutrients and waste products. Cell-cell signaling from the osteocyte sensor cells to the effector cells (osteoblasts or osteoclasts), and the effector cell response – either bone formation or resorption, allow an explanation of local bone gain and loss as well as remodeling in response to fatigue damage as processes supervised by mechanosensitive osteocytes. The osteogenic activity of cultured bone cells has been quantitatively correlated with varying stress stimulations highlighting the importance of the rate of loading. Theoretically a possible mechanism for the stress response by osteocytes is due to strain amplification at the pericellular matrix. Single cell studies on molecular responses of osteocytes provide insight on local architectural alignment in bone during remodeling. Alignment seems to occur as a result of the osteocytes sensing different canalicular flow patterns around cutting cone and reversal zone during loading, thus determining the bone's structure. Disturbances in architecture and permeability of the 3D porous network will affect transduction of mechanical loads to the mechanosensors. Uncovering the cellular and mechanical basis of the osteocyte's response to loading represents a significant challenge to our understanding of cellular mechanotransduction and bone remodeling. In view of the importance of mechanical stress for maintaining bone strength, mechanical stimuli have great potential for providing a therapeutic approach for bone (re)generation.

Download Full-text

The mechanosensitive Piezo1 channel is required for bone formation

eLife ◽

10.7554/elife.47454 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 30

Author(s):

Weijia Sun ◽

Shaopeng Chi ◽

Yuheng Li ◽

Shukuan Ling ◽

Yingjun Tan ◽

...

Keyword(s):

Bone Loss ◽

Bone Formation ◽

Bone Structure ◽

Mechanical Load ◽

Critical Role ◽

Mechanical Stimuli ◽

Mechanical Unloading ◽

Severe Bone Loss ◽

Bona Fide ◽

Osteoblast Lineage

Mechanical load of the skeleton system is essential for the development, growth, and maintenance of bone. However, the molecular mechanism by which mechanical stimuli are converted into osteogenesis and bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer that is critical for various biological processes, plays a critical role in bone formation. Knockout of Piezo1 in osteoblast lineage cells disrupts the osteogenesis of osteoblasts and severely impairs bone structure and strength. Bone loss that is induced by mechanical unloading is blunted in knockout mice. Intriguingly, simulated microgravity treatment reduced the function of osteoblasts by suppressing the expression of Piezo1. Furthermore, osteoporosis patients show reduced expression of Piezo1, which is closely correlated with osteoblast dysfunction. These data collectively suggest that Piezo1 functions as a key mechanotransducer for conferring mechanosensitivity to osteoblasts and determining mechanical-load-dependent bone formation, and represents a novel therapeutic target for treating osteoporosis or mechanical unloading-induced severe bone loss.

Download Full-text

[18F]Fluoride PET Indicates Reduced Bone Formation in Severe Glucocorticoid-induced Osteoporosis

Nuklearmedizin ◽

10.1055/s-0038-1629797 ◽

1998 ◽

Vol 37 (02) ◽

pp. 76-79 ◽

Cited By ~ 8

Author(s):

T. D. Kirchhoff ◽

W. Burchert ◽

J. v. d. Hoff ◽

H. Zeidler ◽

H. Hundeshagen ◽

...

Keyword(s):

Bone Formation ◽

Multiple Organ ◽

High Dose ◽

Multiple Fractures ◽

Glucocorticoid Treatment ◽

Organ Manifestations ◽

Diagnostic Benefit ◽

Sharp Syndrome ◽

18F Fluoride

SummaryA 61-year-old female patient presenting with mixed connective tissue disease (Sharp syndrome), underwent a long-term high dose glucocorticoid treatment because of multiple organ manifestations. Under steroid therapy she developed severe osteoporosis resulting in multiple fractures. A dynamic [18F]fluoride PET study in this patient revealed reduced fluoride influx in non-fractured vertebrae. This finding corresponds to pathogenetic concepts which propose an inhibition of bone formation as major cause of glucocorticoid-induced osteoporosis. In the light of the presented case it seems to be promising to evaluate the diagnostic benefit of [18F]fluoride PET in osteoporosis.

Download Full-text