Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes

Abstract

There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-κB ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-β and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice.

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

“…Functional studies revealed that Ang II could stimulate the differentiation and activity of osteoclasts in vivo [14] and in vitro [15] and aggravate the loss of bone minerals in rats with osteoporosis induced by estrogen deficiency [14]; furthermore, the AT1R knockout mice showed high bone mass [16]. In addition, we recently demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice [17], bone deteriorations of mice with either obstructive nephropathy [18] or type 1 diabetes [19], and others elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model [20] and the steroid-induced osteonecrosis in rabbits [21] as well as the development of postmenopausal osteoporosis in ovariectomized (OVX) animal models [14,22]. Therefore, the emerging evidences demonstrated that the local RAS displays important biological actions in bone tissue.…”

Renin Inhibition Improves Ovariectomy-Induced Osteoporosis of Lumbar Vertebra in Mice

“…13) In addition, we recently demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice, 14) bone deteriorations of mice with either obstructive nephropathy 15) or type 1 diabetes, 16) and others elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model. 17) Therefore, the local RAS displays important biological actions in bone tissue.…”

“…9,10) Functional studies revealed that ANG II could stimulate the differentiation and activity of osteoclasts in vivo 11) and in vitro, 12) and aggravate the loss of bone minerals in rats with osteoporosis induced by estrogen deficiency, 11) furthermore, the ANG II type 1 receptor knockout mice showed high bone mass. 13) In addition, we recently demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice, 14) bone deteriorations of mice with either obstructive nephropathy 15) or type 1 diabetes, 16) and others elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model. 17) Therefore, the local RAS displays important biological actions in bone tissue.…”

Involvement of Renin–Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice

“…Our further animal studies demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice, 11) and bone deteriorations of mice with either obstructive nephropathy 12) or type 1 diabetes. 13) Other groups elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model, 14) and the steroid-induced osteonecrosis in rabbits 10) as well as the development of postmenopausal osteoporosis in ovariectomized (OVX) animal models 15,16) and glucocorticoid-induced osteoporosis. 9) Therefore, it concludes that the local RAS exists in bone tissue and plays an important role in local bone metabolism.…”

“…)), significantly elevated serum level of tartrate-resistant acid phosphatase, and had a trend to decrease bone mineral density of trabecular bone and damage microarchitecture of proximal tibial head and distal femoral end in type 1 diabetic mice. 13) In view of the contradictory effects of ACEI on bone health from human and animal studies, we are keen to know the effects of ACEI on bone tissue of normal mice. Thus, this study was performed to investigate the effect of ACEI, captopril, on bone histology and the action of captopril on the components of skeletal RAS in normal male mice.…”