Angiotensin II Type 2 Receptor Blockade Increases Bone Mass

Abstract

Renin angiotensin system (RAS) regulates circulating blood volume and blood pressure systemically, whereas RAS also plays a role in the local milieu. Previous in vitro studies suggested that RAS may be involved in the regulation of bone cells. However, it was not known whether molecules involved in RAS are present in bone in vivo. In this study, we examined the presence of RAS components in adult bone and the effects of angiotensin II type 2 (AT2) receptor blocker on bone mass. Immunohistochemistry revealed that AT2 receptor protein was expressed in both osteoblasts and osteoclasts. In addition, renin and angiotensin II-converting enzyme were expressed in bone cells in vivo. Treatment with AT2 receptor blocker significantly enhanced the levels of bone mass, and this effect was based on the enhancement of osteoblastic activity as well as the suppression of osteoclastic activity in vivo. These results indicate that RAS components are present in adult bone and that blockade of AT2 receptor results in alteration in bone mass.Osteoporosis is one of the major diseases associated with aging. This disease is based on the imbalance between the two major activities, i.e. bone formation and bone resorption. Systemic signals such as parathyroid hormone (PTH) 3 and vitamin D are the major regulators of the maintenance of bone mass and blood calcium (1-3). In addition, bone mass levels are also determined by a central nervous control through the activities of sympathetic tone on both bone formation and resorption sides (4 -7). In the local milieu of bone, two major types of cells, osteoblasts and osteoclasts, are located in close proximity, exchange their signals, and coordinately resorb and form bone matrix (8). Such events are controlled by molecules present in the local microenvironment. These include cytokines, their modulators, and matrix proteins secreted by osteoblasts and osteoclasts (9 -11). However, the bone environment is quite heterogeneous, and there are also cells other than these two types. Microvasculatures are serving as a root to supply osteoclast progenitors, which are derived from hematopoietic lineage cells. Vasculatures in bone are also considered to give rise to progenitors for osteoblastic cells from their perivascular regions (12). In addition to the anatomical relationship between the vascular cells and bone cells, these cells may be functionally involved in the coordinate regulation of bone mass.Recent clinical studies indicated that beta blockers and antihypertension drugs would reduce the risk of bone fractures in the elderly populations (13,14). This suggests a possible link between vascular and skeletal systems. Renin angiotensin system (RAS) is operating not only systemically but also locally in several tissues, and bone microenvironments have been studied in this regard (15,16). Osteoblasts and osteoclasts express angiotensin II type 1 receptor in cell cultures (17-19), suggesting the existence of local RAS in bone. However, whether RAS components are expressed in bone in vivo is not known.A...

Involvement of the Skeletal Renin-Angiotensin System in Age-Related Osteoporosis of Ageing Mice

“…19) Efforts need to be made to screen those at risk of osteoporosis and identify the potential pathological mechanisms for age-related osteoporosis. Our study is the first to report the gene expression of RAS components in bone tissue by the polymerase chain reaction, in accordance with the results which showed the protein expression of ACE, rennin and angiotensin II receptors in the tibia 6) and femur 20) of mice. The objective of the present study was to elucidate the potential pathological role of local RAS during the process of age-related bone deterioration.…”

“…5) Recent studies have shown that such components of RAS as renin, ACE, and Ang II receptors are expressed in the skeleton. 6) Functional studies have revealed that Ang II could stimulate the differentiation and activity of osteoclasts in vivo 7) and in vitro, 8) and that the activation of RAS induced high-turnover osteoporosis with accelerated bone resorption.…”

“…2,6,7,9) Epidemiological studies have reported the benefit of such antihypertensive drugs as ACE inhibitors and angiotensin II receptor blockers (ARB) for increasing the bone mass and decreasing the risk of bone fractures. 10,11) We therefore hypothesized that bone RAS might be a local regulating system for bone metabolism.…”

Partial Agonist, Telmisartan, Maintains PPARγ Serine 112 Phosphorylation, and Does Not Affect Osteoblast Differentiation and Bone Mass

“…RAS is recognized as contributing to the development of osteoporosis independently of hypertension [17]–[19], and a blockage of this system either at the level of angiotensin enzyme inhibitor (ACEI) or at the level of angiotensin receptors proved to be beneficial for bone [20], [21]. Beside its anti-hypertensive activity, TEL has a unique ability to bind and activate PPARγ [22], [23] and has a beneficial effects on insulin sensitivity in humans [24]–[26] and rodents [27].…”

Type XII collagen regulates osteoblast polarity and communication during bone formation

“…The whole tissue and cell lysate preparation and immunoblot were performed as previously described (Izu et al, 2009) using rabbit anti-type XII collagen (1:1,000 dilution; KR33), rabbit anti-Cx43 (1:10,000 dilution; Sigma-Aldrich), rabbit anti-mouse collagen I (1:1,000 dilution; Millipore), rabbit anti-Cad11 (1:250 dilution; Invitrogen), rabbit anti-N-cadherin (1:1,000 dilution; Cell Signaling Technology), 0.1 µg/ml of goat anti-mouse osteopontin (R&D Systems), goat anti-osteocalcin (1:100 dilution; Santa Cruz Biotechnology, Inc.), mouse anti--actin (1:5,000 dilution; Millipore), and anti-mouse or anti-rabbit HRP-conjugated secondary antibodies (GE Healthcare).…”