Pal, Shripad Nagesh (2009) Role of osteo-progenitors in the pathogenesis of vascular calcification. PhD thesis, James Cook University.

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Abstract

Vascular calcification, until recently, was considered to be a passive process which occurred as a nonspecific response to tissue injury or necrosis. Since the severity of vascular calcification has been correlated with that of atherosclerosis and its risk factors, it was postulated that the process is linked to these events. However recent findings from a number of mouse model studies suggest that the mechanisms involved in vascular calcification may be distinct from those underlying atherosclerosis.

Current theories regarding the pathogenesis of vascular calcification suggest a number of possible mechanisms. These include passive models in which vascular calcification is observed as a result of loss of molecular inhibitors and those where active cell mediated process is involved. Calcification has also been reported as result of apoptosis or death of vascular smooth muscle cells (VSMC). Current evidence favours a cell mediated mechanism of vascular calcification.

The origin of the cells responsible for vascular calcification is not clearly defined. One novel source of cells controlling vascular calcification is from the bone marrow (BM). A circulating immature BM-derived population has been identified. A small subset of this BM population has been reported to possess bone forming properties invitro and hence called osteo-progenitors. In the present investigation, it was hypothesized that these circulating osteo-progenitors contribute to vascular calcification. It was postulated that the osteo-progenitors are recruited from the BM environment under the influence of stem cell mobilising cytokines such as stromal cell derived factor-1 α (SDF-1α ), granulocyte-colony stimulating factor (GCSF) and stem cell factor (SCF). Further, it was suggested that these stem cell mobilising cytokines facilitate the homing of immature circulating osteo-progenitors to vascular lesions and contribute to calcification.

These hypotheses were tested in two mouse models and one human patient cohort. The aims of the investigation included: a) To establish a suitable mouse model for vascular calcification studies. b) To assess the association of the circulating osteo-progenitor population with the severity of aortic calcification in mouse models. c) To identify if the osteo-progenitor population was deposited within the vasculature at sites of vascular calcification. d) To assess the relationship between the circulating osteo-progenitor population and aortic calcification in a human patient group suffering from peripheral artery disease. e) To assess the relationship between the stem cell mobilising cytokines and the severity of vascular calcification in a mouse model and a human patient cohort.

The findings of this work suggest, for the first time, an association between circulating osteocalcin positive mononuclear cells (OCN+ MNC) and aortic calcification in two mouse models and a human patient cohort diagnosed with peripheral artery disease. It was found that the severity of vascular calcification was increased in 52 week old osteoprotegerin knockout (OPG-/-) mice and even more elevated in younger (14 week old) OPG-/- mice receiving controlled doses of calcitriol. It was further observed that in both mouse models the percentage of circulating OCN+ MNC was correlated to the aortic calcium content. These results suggest a possible role for BM-derived osteo-progenitors in vascular calcification. Itwas also observed that OCN+ population deposited within the vasculature was directly associated with the severity of extractable aortic calcium in the OPG-/- mouse model. These results suggest a three-way association between osteo-progenitor population in circulation, its cellular deposition within vasculature and the severity of aortic calcification.

The investigation undertaken in the human patient cohort also supported the initial hypothesis and confirmed the research findings obtained from the two mouse models. In the patient study the percentage of circulating OCN+ MNC was observed to be associated with the severity of infra-renal aortic calcification.

The present study also supported the hypothesis that the stem cell mobilizing cytokines could be involved with the release of osteo-progenitors and may facilitate their homing to the vasculature. The concentrations of SDF-1α , G-CSF and SCF were associated with the percentage of circulating OCN+ MNC and the severity of aortic calcification in the mouse models and patient cohort investigated. These results suggest that the BM- derived osteo-progenitors are mobilised into the peripheral circulation from the marrow environment under the influence of these cytokines. Further, the circulating osteo-progenitors may home to vascular lesions and differentiate into bone-forming cells. This process may contribute to the pathogenesis of vascular calcification.

Further work, however, is necessary to confirm the role of these BM-derived immature cells in vascular calcification as there are a number of limitations of the present investigation. Firstly, both mouse models employed were based on OPG deficiency. Thus it is possible that the increased OCN+ MNC was related to this rather than the aortic calcification in these animals. Secondly, the role of OPG within the vasculature is also not entirely clear. While depletion of OPG in mouse models is reported to induce vascular calcification, in patients serum OPG levels are positively associated with peripheral artery disease. This difference in results between mouse models and human patient illustrates the current uncertainty regarding the role of OPG in cardiovascular disease. The patient group investigated in this study was small. A larger group would be ideal to confirm the association between circulating osteo-progenitors and aortic calcification. The absence of a healthy control group is a further limitation of the human investigation.

Overall, the current research suggests an important new mechanism underlying vascular calcification with implications for treatment. Results obtained from this study may also be useful in the investigation of other pathology types, and may assist in establishing collaboration with external groups. Since vascular calcification is also linked to other clinical conditions such as atherosclerosis, diabetes, obesity and bone related disorders, this investigation can build on those areas within research groups with broader clinical perspectives.

Item ID:	17239
Item Type:	Thesis (PhD)
Keywords:	vascular calcification, pathogenesis, osteo-progenitors, aorta, bone marrow, stem cell mobilising cytokines, osteocalcin positive mononuclear cells
Date Deposited:	31 May 2011 04:25
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 50% 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110299 Cardiovascular Medicine and Haematology not elsewhere classified @ 50%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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