Role of Osteoprotegerin in Arterial Calcification

Abstract

Objectives-Enhanced osteoclastogenesis, increased bone resorption, and osteoporosis have been reported in osteoprotegerin-deficient (OPG (Ϫ/Ϫ)) mice. OPG (Ϫ/Ϫ) mice available in Japan usually do not show vascular calcification. We have found that arterial calcification can be quickly induced by a simple procedure in OPG (Ϫ/Ϫ) mice. Methods and Results-Male OPG (Ϫ/Ϫ), OPG (ϩ/Ϫ), and OPG (ϩ/ϩ) mice were fed a high phosphate diet from 6 to 10 weeks after birth, and then 1␣,25-dihydroxyvitamin D3 (calcitriol) was injected for 3 days. We found that severe calcification developed in the media of the aorta in OPG (Ϫ/Ϫ) mice. Under electron microscopy, calcium deposits were observed in the cytoplasm and extracellular matrix of vascular smooth muscle cells (VSMCs Key Words: osteoprotegerin Ⅲ alkaline phosphate Ⅲ vascular smooth muscle cells Ⅲ calcium deposits V ascular calcification, which is frequently observed in patients with end-stage renal disease, diabetes, aging, and osteoporosis, can also lead to cardiovascular diseases and even sudden death. 1-3 Until recently, vascular calcification was considered to be a passive process that occurred as a nonspecific response to tissue injury or necrosis. Now it is becoming increasingly clear that vascular calcification is an actively regulated process that resembles bone metabolism and involves alkaline phosphatase (ALP) and other bonerelated proteins. 4 -7 Osteoprotegerin (OPG) is abundantly produced by osteoblasts at the bone surface and inhibits osteoclast activity, working as a key regulator of bone homeostasis. 8,9 Since it has been reported that OPG (Ϫ/Ϫ) mice exhibit severe osteoporosis attributable to enhanced osteoclastogenesis, OPG is considered to be a protective factor in bone metabolism. 10,11 In the vasculature, the function of OPG is unknown because it is unclear whether vascular calcification takes place in OPG (Ϫ/Ϫ) mice or not. 10,11 Moreover, it was reported that the serum OPG level is associated with the presence and severity of coronary artery disease (CAD). 12 It remains to be clarified whether OPG is involved in the progression of CAD or whether the upregulation of serum OPG concentration is a compensatory mechanism. ALP is a crucial enzyme for initiating mineralization in bone and is present in systemic arteries, arterioles, and some capillaries. 13 It is possible that this enzyme plays a role in arterial calcification by the same mechanism of action as that in bone. 14 Activation of ALP in the arterial wall may result in enhanced vascular calcification.It is well known that either an elevated serum phosphate level or treatment with high doses of vitamin D induces vascular calcification in animal models as well as in humans. 15,16 In the present study, using OPG (Ϫ/Ϫ) mice, we established a mouse model in which arterial calcification can be quickly induced by treatment with a high phosphate diet plus 1␣,25-dihydroxyvitamin D3 (calcitriol) injection, and this model allowed us to perform detailed pathological and biochemical examinations at desired tim...

Vascular Calcification

“…110 OPG was shown to inhibit ALP activity in aortic tissue and prevent the progression of medial layer vascular calcification. 111 Similar results were observed in the diabetic LdlrϪ/Ϫ mouse model, showing again OPG administration diminishes vascular calcium accumulation, potentially through immunomodulatory actions upon dietinduced low-grade mural inflammation. 112 Although little is known about the direct effect of OPG on VSMCs, it is important to understand further its role in osteogenesis and its involvement in the inflammatory response, which is important for the osteoblastic differentiation of VSMCs.…”

Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors

“…In this context, the use of either recombinant OPG or a monoclonal antibody against RANKL has been very powerful at alleviating bone erosion in the above mentioned diseases [49,[51][52][53][54][55]. Moreover, recent studies have also shown that the OPG/RANKL ratio plays an important role in controlling vascular calcification [56][57][58][59]: a low OPG/RANKL ratio was correlated with increased vascular smooth muscle cell calcification.…”

Vascular Calcification

“…14 These findings are in further agreement with the frequent arterial dissection and rupture in mouse models with aortic vascular calcification. 15,16 Thus, vascular calcification introduces compliance mismatch that can promote mechanical failure due to stress concentration at the interfaces of calcium deposits with softer plaque components.…”