Mechanical loading thresholds for lamellar and woven bone formation

Despite the strong connection between angiogenesis and osteogenesis in skeletal repair conditions such as fracture and distraction osteogenesis, little is known about the vascular requirements for bone formation after repetitive mechanical loading. Here, established protocols of damaging (stress fracture) and nondamaging (physiological) forelimb loading in the adult rat were used to stimulate either woven or lamellar bone formation, respectively. Positron emission tomography was used to evaluate blood flow and fluoride kinetics at the site of bone formation. In the group that received damaging mechanical loading leading to woven bone formation (WBF),15O water (blood) flow rate was significantly increased on day 0 and remained elevated 14 days after loading, whereas18F fluoride uptake peaked 7 days after loading. In the group that received nondamaging mechanical loading leading to lamellar bone formation (LBF),15O water and18F fluoride flow rates in loaded limbs were not significantly different from nonloaded limbs at any time point. The early increase in blood flow rate after WBF loading was associated with local vasodilation. In addition, Nos2 expression in mast cells was increased in WBF-, but not LBF-, loaded limbs. The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester was used to suppress NO generation, resulting in significant decreases in early blood flow rate and bone formation after WBF loading. These results demonstrate that NO-mediated vasodilation is a key feature of the normal response to stress fracture and precedes woven bone formation. Therefore, patients with impaired vascular function may heal stress fractures more slowly than expected.

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Effect of mechanical loading on insulin-like growth factor-I gene expression in rat tibia

Journal of Endocrinology ◽

10.1677/joe.1.06880 ◽

2007 ◽

Vol 192 (1) ◽

pp. 131-140 ◽

Cited By ~ 68

Author(s):

Christianne M A Reijnders ◽

Nathalie Bravenboer ◽

Annechien M Tromp ◽

Marinus A Blankenstein ◽

Paul Lips

Keyword(s):

Bone Formation ◽

Mrna Expression ◽

Mechanical Loading ◽

Mechanical Stimulation ◽

Molecular Mechanisms ◽

Bone Marrow Cells ◽

Mechanical Stimuli ◽

Igf I ◽

Female Wistar Rats ◽

Tibia Shaft

Mechanical loading plays an essential role in maintaining skeletal integrity. Mechanical stimulation leads to increased bone formation. However, the cellular and molecular mechanisms that are involved in the translation of mechanical stimuli into bone formation, are not completely understood. Growth factors and osteocytes, which act as mechanosensors, play a key role during the bone formation after mechanical stimulation. The aim of this study was to characterize the role of IGF-I in the translation of mechanical stimuli into bone formation locally in rat tibiae. Fifteen female Wistar rats were randomly assigned to three groups (n = 5): load, sham-loaded, and control. The four-point bending model of Forwood and Turner was used to induce a single period of mechanical loading on the tibia shaft. The effects of mechanical loading on IGF-I mRNA expression were determined with non-radioactive in situ hybridization on decalcified tibiae sections, 6 h after the loading session. Endogenous IGF-I mRNA was expressed in trabecular and cortical osteoblasts, some trabecular and sub-endocortical osteocytes, intracortical endothelial cells of blood vessels, and periosteum. Megakaryocytes, macrophages, and myeloid cells also expressed IGF-I mRNA. In the growth plate, IGF-I mRNA was located in proliferative and hypertrophic chondrocytes. Mechanical loading did not affect the IGF-I mRNA expression in osteoblasts, bone marrow cells, and chondrocytes, but the osteocytes at the endosteal side of the shaft showed a twofold increase of IGF-I mRNA expression. The proportion of IGF-I mRNA positive osteocytes in loaded tibiae was 29.3 ± 12.9% (mean ± s.d.; n = 5), whereas sham-loaded and contra-lateral control tibiae exhibited 16.7 ± 4.4% (n = 5) and 14.7 ± 4.2% (n = 10) respectively (P < 0.05). Lamellar bone formation after a single mechanical loading session was observed at the endosteal side of the shaft. In conclusion, a single loading session results in a twofold up-regulation of IGF-I mRNA synthesis in osteocytes which are present in multiple layers extending into the cortical bone of mechanically stimulated tibia shaft 6 h after loading. This supports the hypothesis that IGF-I, which is located in osteocytes, is involved in the translation of mechanical stimuli into bone formation.

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Platelet-rich plasma decreases fibroblastic activity and woven bone formation with no significant immunohistochemical effect on long-bone healing: An experimental animal study with radiological outcomes

Journal of Orthopaedic Surgery ◽

10.1177/2309499018802491 ◽

2018 ◽

Vol 26 (3) ◽

pp. 230949901880249 ◽

Cited By ~ 2

Author(s):

İbrahim Deniz Canbeyli ◽

Rahmi Can Akgun ◽

Orcun Sahin ◽

Aysen Terzi ◽

İsmail Cengiz Tuncay

Keyword(s):

Bone Formation ◽

Callus Formation ◽

Platelet Rich Plasma ◽

Long Bone ◽

Proliferation Index ◽

Fibroblast Proliferation ◽

Ki 67 ◽

Woven Bone ◽

Group B ◽

Mature Bone

Purpose: This study aimed to analyze the immunohistochemical effect of platelet-rich plasma (PRP) on healing of long-bone fractures in terms of bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), the Ki-67 proliferation index, and radiological and histological analyses. Methods: Sixteen adult rabbits, whose right femoral diaphysis was fractured and fixed with Kirschner wires, were randomly divided into two groups, control and PRP (groups A and B, respectively). PRP was given to group B at 1 week postoperatively, and all animals were euthanized after 12 weeks. Radiographic evaluations were performed periodically. Cortical callus formation, chondroid and woven bone area percentages, osteoblastic and fibroblastic activities, and mature bone formation were examined. The depths of BMP-2 and VEGF staining were measured. The Ki-67 proliferation index was also calculated. Results: The mean radiological union score of group B was significantly higher than that of group A. There were also statistically significant differences between groups A and B in terms of cortical callus formation, woven bone area percentage, fibroblast proliferation, and mature bone formation. Group B had significantly more cortical callus and mature bone formation with less woven bone and fibroblast proliferation. Immunohistochemical analysis revealed no statistically significant difference between the groups in terms of BMP-2 and VEGF staining and the Ki-67 index. Conclusions: PRP had no effect on BMP-2 or VEGF levels with no increase in the Ki-67 proliferation index, although its application had a positive effect on bone healing by increasing callus and mature bone formation with decreased woven bone and fibroblast proliferation.

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Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis

10.21203/rs.3.rs-888146/v1 ◽

2021 ◽

Author(s):

Bingzi Dong ◽

Masahiro Hiasa ◽

Itsuro Endo ◽

Yukiyo Ohnishi ◽

Takeshi Kondo ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Bone Formation ◽

Mechanical Loading ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Mechanical Unloading ◽

Enhanced Expression ◽

Wnt Inhibitors ◽

Interleukin 11

Abstract Exercise offers mechanical loading to the bone, while it stimulates energy expenditure in the adipose tissue. Thus, bone may secrete a factor to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is expressed in the bone, upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Systemic IL-11 deletion (IL-11−/−) exhibited reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. Enhancement of bone resorption under mechanical unloading was unaffected. Unexpectedly, IL-11−/− mice showed increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice showed reduced serum IL-11, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11−/− mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre; IL-11fl/fl mice exhibited no abnormality. Thus, IL-11 from osteoblast/osteocyte controls both osteogenesis and systemic adiposity in response to mechanical loading. These findings may bring new therapeutic approaches to osteoporosis and metabolic syndrome.

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