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REVIEW ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 2  |  Page : 345-350

A study of bone–vascular axis in health and disease


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Shebin El-Kom Teaching Hospital, Ministry of Health, Menoufia, Egypt

Date of Submission18-Sep-2021
Date of Decision21-Oct-2021
Date of Acceptance24-Oct-2021
Date of Web Publication27-Jul-2022

Correspondence Address:
Alaa A. Ali Al Sayedb
Al-Tawhid Mosque Street, Quesna, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_171_21

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  Abstract 


Objectives
The aim was to study bone–vascular axis in health and disease.
Data sources
Medline databases (PubMed and MedScape) and all materials available in the internet were searched. The search was performed in September 2021.
Study selection
The initial search presented 120 articles. The number of studies that met the inclusion criteria was 21. The articles included both sexes and patients with bone–vascular disease.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest.
Data synthesis
Significant data were collected. Then a structured review was performed.
Finding
In total, 21 potentially relevant publications were included; it was found that cardiovascular and bone disease are pathophysiologically interrelated.
Conclusions
Cardiovascular and bone disease are pathophysiologically interrelated, even though a full understanding of the mechanisms underlying this relationship is still lacking. A better understanding of the biological link between the two processes could lead to the development of new compounds that act on both vessels and bone. Meanwhile, it would seem reasonable to consider cardiovascular disease screening in patients with advanced bone demineralization, as well as careful monitoring for signs and symptoms of cardiovascular disease in chronic kidney disease patients.

Keywords: axis, bone, disease, health, vascular


How to cite this article:
Shoeib SA, El-Shebiny EM, Zahran ES, Al Sayedb AA. A study of bone–vascular axis in health and disease. Menoufia Med J 2022;35:345-50

How to cite this URL:
Shoeib SA, El-Shebiny EM, Zahran ES, Al Sayedb AA. A study of bone–vascular axis in health and disease. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:345-50. Available from: http://www.mmj.eg.net/text.asp?2022/35/2/345/352133




  Introduction Top


Bone is of crucial importance for the human body, providing skeletal support, and serving as a home for the formation of hematopoietic cells and as a reservoir for calcium and phosphate. Bone is also continuously remodeled in vertebrates throughout life[1].

Bone is a mineralized connective tissue that exhibits four types of cells: osteoblasts, bone lining cells, osteocytes, and osteoclasts. Bone exerts important functions in the body, such as locomotion, support and protection of soft tissues, calcium and phosphate storage, and harboring of bone marrow[2].

Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in aging organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled[3].

Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, that is, osteonecrosis, osteoporosis, atherosclerosis, or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, successful bone regeneration in both approaches largely depends on a proper blood supply[4].

There is a strong relation between bone and vascular system, the concept of the bone–vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent hematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (the so-called diabetic mobilopathy), with possible clinical implications. Clinical entity of chronic kidney disease–mineral and bone disorders and its cardiovascular burden is studied. Bone is thus becoming a recurrently considered paradigm for different interorgan communications that needs to be considered in patients with complex diseases[5],[6],[7].

The aim was to study bone–vascular axis in health and disease.


  Materials and methods Top


This review was conducted according to guidance developed by the center for review and dissemination. It was used to assess the methodology and outcome of the studies. The study was approved by the ethics committee.

Search strategy

Search was performed in several databases. It included Medline database (articles in Medscape, PubMed) and also materials available on the internet. The search was performed on September 2021 and included all articles published. We used axis, bone, disease, health, and vascular as the search terms. We also examined reference lists in relevant publications. The search was performed in the electronic databases from 2011 to 2021.

Study selection

All studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

  1. Case–control studies, cross-sectional studies, cohort studies, or systematic reviews and meta-analyses.
  2. Both sexes included.
  3. Patients with bone–vascular disease.
  4. Articles in English.


Exclusion criteria:

  1. The patients who had any other diseases that may affect the results.
  2. Articles not in English.


The article title and abstract were initially screened. Then the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies.

Data extraction

Data were extracted independently and in duplicate from eligible studies using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusions and comments on each study were made.

The analyzed publications were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force and in addition to the evidence pyramid [Figure 1].
Figure 1: Pyramid of evidence-based medicine.

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US Preventive Services Task Force:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial.
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization.
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
  5. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.


  Result Top


In total, 120 potentially relevant publications were identified; 99 articles were excluded as they did not meet our inclusion criteria [Figure 2]. A total of 21 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. The significant data were collected. A structured systematic review was performed and the results tabulated as provided in [Table 1].
Figure 2: Flowchart of study selection.

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Table 1: Characteristics and results of studies included in the review article

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  Discussion Top


According to Boskey and Imbert[8] despite its inert appearance, bone is a highly dynamic organ that is continuously resorbed by osteoclasts and neoformed by osteoblasts. There is evidence that osteocytes act as mechanosensors and orchestrators of this bone remodeling process. Bone is a multifunctional tissue that serves as mechanical support and protection, is an essential part of hematopoiesis and mineral metabolism, and has a role as an endocrine organ. Bone is able to resist deformation from impact loading, but at the same time, it is also able to absorb or dissipate energy by changing shape without cracking.

Zhang et al.[9] reported that bone is a composite material whose extracellular matrix consists of mineral (65%), water (10%), lipids (1%), and organic material (25%), the latter being composed predominantly of type I collagen (90%) and noncollagenous proteins (10%). These components have both mechanical and metabolic functions, and the composition and architectural features vary with age, sex, species, and site, which is studied, and it can be affected by disease and treatment.

Corradetti et al.[10] reported that the largest proportion is occupied by the mineral phase consisting predominately of a nanocrystalline, highly substituted, poorly crystalline analog of the hydroxylapatite as demonstrated by radiograph diffraction over 60 years ago.

Bonewald[11], osteoblasts are engaged in bone formation. The extracellular matrix synthesized by osteoblasts is known as osteoid when first deposited and not yet mineralized, but it is subsequently mineralized through the accumulation of calcium phosphate in the form of hydroxyapatite.

Sabine et al.[12], osteoclasts are multinucleated giant cells responsible for bone resorption. Ultrastructurally, the multiple nuclei are surrounded by many mitochondria, endoplasmic reticulum, and a well-developed Golgi apparatus.

Tomer et al.[13], blood vessels organize into tree-like structures. Large arteries carry oxygenated blood away from the heart and branch into smaller caliber arterioles that feed into extensive capillary networks. Venules drain capillaries and converge into larger veins to return oxygen-depleted blood to the heart. Blood is transferred through the pulmonary artery to the lungs for reoxygenation.

Sulston and Cawthorn[14], in the bone marrow, the less permeable arteries maintain hematopoietic stem cells in a quiescent state, whereas the more permeable sinusoidal vessels promote hematopoietic stem cell activation and differentiation, as penetrating blood plasma increases the formation of reactive oxygen species. Unlike most blood vessels, lymphatic capillaries are tasked with fluid uptake and are thus highly permeable. They are equipped with button-like junctions and anchoring filaments, which together facilitate fluid uptake when the interstitial pressure is high. In the small intestine, lymphatic capillaries (lacteals) are further specialized for the absorption of dietary lipids.

Karsenty and Olson[15], bone was perceived as the repository of ions mainly calcium (Ca) and phosphate (P), whose movement into and out of the bone was regulated by the parathyroid hormone and active vitamin D through actions on osteoblasts and osteoclasts. This view changed with the discovery that osteocytes, previously thought to be inactive, in fact orchestrate osteoblast and osteoclast activity, including the synthesis of proteins with hormonal or hormone-like properties. Accordingly, bone is now recognized as an endocrine organ.

Rosen[16], osteocalcin (OCN) is the most expressed noncollagenous protein in the bone matrix, synthesized by osteoblasts. Several studies have shown an association between OCN and cardiovascular risk factors such as insulin resistance and dyslipidemia.

Ghadiri-Anari et al.[17], the relationship between OCN and atherosclerosis in humans has been suggested in different studies. In a study conducted in healthy postmenopausal women, there was an increased prevalence of carotid atherosclerosis in those with OCN levels above the median and low bone mineral density. Moreover, some evidence has shown that OCN is expressed in the calcific atherosclerotic lesions and in the vascular SMC of the vessel wall, suggesting a potential role in the differentiation of vascular SMC into osteogenic cells.

Rochette et al.[18], osteoprotegerin is a member of the TNF superfamily that acts by binding RANKL and TRAIL. Its role in bone metabolism is to inhibit osteoclastic bone resorption, a role it enacts through its presentation as a 'decoy receptor' for RANKL, preventing its binding to RANK and stimulating osteoclast activation. Indeed, elevated serum osteoprotegerin levels are associated with higher BMD. Circulating osteoprogenitor cells, a member of the monocytic family, express OCN on their surface and exhibit increased abundance in patients with cardiovascular disease. Because of their pro-calcific phenotype, these cells contribute to the development of vascular calcification and atherosclerosis under normal conditions. Patients with diabetes show elevated levels of OCN+circulant monocytes compared with controls, especially in the presence of atherosclerotic cardiovascular disease.

Pietrzyk et al.[19], sclerostin is a soluble factor secreted by osteocytes. It regulates bone turnover by inhibiting Wnt/β-catenin signaling, which promotes the differentiation and proliferation of osteoblasts. Sclerostin is also able to stimulate osteoblast apoptosis through the activation of caspases. Therefore, when sclerostin action is suppressed, osteogenesis is indirectly stimulated. Loss of sclerostin gene function is related to diseases characterzsed by a hyperostosis process.

Lampropoulos et al.[20], osteopontin is a structural glycoprotein of the bone matrix. Because of its high number of aspartic acid residues, it can bind calcium and hydroxyapatite ions, inhibiting crystal formation. In addition, it can bind several integrin receptors, especially integrin β3 on the surface of osteoclasts. This binding leads to a decrease in calcium concentration and to the activation of carbonic anhydrase II, both required for osteoclastic activation.

López-Otín et al.[21], aging is characterized by the progressive loss of overall physiological integrity, typically resulting in decreased bone mineral density and subsequent susceptibility to fractures. Several cross-sectional and longitudinal studies demonstrate an independent and inverse relationship between bone mineral density and atherosclerotic burden or arteriopathy.


  Conclusion Top


Improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extra skeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centered perspective. A fundamental understanding of bone–vascular interactions will be necessary to develop new strategies that safely and efficaciously enhance bone formation in the settings of malignancy, fracture nonunion, open epiphyses of childhood and the arteriosclerotic vasculopathy of diabetes, uremia, rheumatoid arthritis, and advanced age.

Cardiovascular and bone disease are both physiologically interrelated, even though a full understanding of the mechanisms underlying this relationship is still lacking. A better understanding of the biological link between the two processes could lead to the development of new compounds that act on both vessels and bone. Meanwhile, it would seem reasonable to consider cardiovascular disease screening in patients with advanced bone demineralization, as well as careful monitoring for signs and symptoms of cardiovascular disease in chronic kidney disease patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Thompson B, Towler D. Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol 2012; 8:529–543.  Back to cited text no. 1
    
2.
Dallas S, Prideaux M, Bonewald L. The osteocyte: an endocrine cell and more. Endocr Rev 2013; 34:658–690.  Back to cited text no. 2
    
3.
Rhee Y, Bivi N, Farrow E. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone J 2011; 49:636–643.  Back to cited text no. 3
    
4.
Kusumbe A, Ramasany S, Adams R. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 2014; 507:223–328.  Back to cited text no. 4
    
5.
Filipowska J, Tomaszewski K, Niedzwiedzki L. The role of vasculature in bone development, regeneration and proper systemic functioning. Review paper. Angiogenesis 2017; 20:291–302.  Back to cited text no. 5
    
6.
Mandair G, Morris M. Contributions of Raman spectroscopy to the understanding of bone strength. Bonekey Rep 2015; 2015:620.  Back to cited text no. 6
    
7.
Donnelly E, Meredith D, Nguyen J. Bone tissue composition varies across anatomic sites in the proximal femur and the iliac crest. J Orthop Res 2012; 30:700–706.  Back to cited text no. 7
    
8.
Boskey A, Imbert L. Bone quality changes associated with aging and disease: a review. Ann N Y Acad Sci 2017; 1410:93.  Back to cited text no. 8
    
9.
Zhang W, Wu Y, Chen H, Yu D, Zhao J. Neuroprotective effects of SOX5 against ischemic stroke by regulating VEGF/PI3K/AKT pathway. Gene 2021; 767:145148.  Back to cited text no. 9
    
10.
Corradetti B, Taraballi F, Powell S. Osteoprogenitor cells from bone marrow and cortical bone: understanding how the environment affects their fate. Stem Cells Dev 2015; 24:1112–1123.  Back to cited text no. 10
    
11.
Bonewald L. Osteocytes. In: Rosen CJ, editor. Primer on the metabolic bone dis-eases and disorders of mineral metabolism. 8th ed. New York: Wiley; 2013. 34–41.  Back to cited text no. 11
    
12.
Sabine A, Saygili Demir C, Petrova TV. Endothelial cell responses to biomechanical forces in lymphatic vessels. Antioxid Redox Signal 2016; 25:451–465.  Back to cited text no. 12
    
13.
Tomer I, Shiri G, Joel A. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 2016; 532:323–328.  Back to cited text no. 13
    
14.
Sulston R, Cawthorn W. Bone marrow adipose tissue as an endocrine organ: close to the bone? Horm Mol Biol Clin Investig 2016; 28:21–38.  Back to cited text no. 14
    
15.
Karsenty G, Olson E. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 2016; 164:1248–1256.  Back to cited text no. 15
    
16.
Rosen C. Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed. New York: Wiley; 2013. 34–41.  Back to cited text no. 16
    
17.
Ghadiri-Anari A, Mortezaii-Shoroki Z, Modarresi M, Dehghan A. Association of lipid profile with bone mineral density in postmenopausal women in Yazd province. Int J Reprod Biomed 2016; 14:597.  Back to cited text no. 17
    
18.
Rochette A, Alexandre M, Eve R. The role of osteoprotegerin and its ligands in vascular function. Int J Mol Sci 2019; 20:705.  Back to cited text no. 18
    
19.
Pietrzyk K, Mike S, Jerzy C. Sclerostin: intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med. 2017; 26:1283–1291.  Back to cited text no. 19
    
20.
Lampropoulos A, Ioanna P, David P. Osteoporosis a risk factor for cardiovascular disease? Nat Rev Rheumatol 2012; 8:587–598.  Back to cited text no. 20
    
21.
López-Otín C, Blasco M, Partridge L. The hallmarks of aging. Cell 2013; 153:1194–1217.  Back to cited text no. 21
    


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