Continuous Parathyroid Hormone Induces Cortical Porosity in the Rat: Effects on Bone Turnover and Mechanical Properties

Lotinun, Sutada; Evans, Glenda L.; Bronk, James T.; Bolander, Mark E.; Wronski, Thomas J.; Ritman, Erik L.; Turner, Russell T.

doi:10.1359/jbmr.040404

Cited by 61 publications

(50 citation statements)

References 33 publications

(31 reference statements)

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“…PTH in aged OVX rats restores bone volume by thickening the existing trabeculi without increasing the trabecular connectivity (40,41), although not influencing the trabecular mechanical strength (42). PTH also improves rigidity and stiffness of bone, but makes them more brittle, with less elasticity and less deformation before fracture (43). BMP-6 improves the trabecular microarchitecture in aged OVX rats by increasing trabecular thickness, trabecular number, and in particular, trabecular connectivity.…”

Section: Discussionmentioning

confidence: 99%

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

Šimić

Culej

Orlić

et al. 2006

Journal of Biological Chemistry

100

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Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17␤-estradiol (E 2 ) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125 I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E 2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats.Bone loss during aging and after menopause in women is known to result from an imbalance between bone formation and resorption leading to altered bone microarchitecture and excess bone fragility. Inferior bone strength and increased bone fracture rate of bone in patients with osteoporosis might be associated with decreased osteoinductive and thus self-regenerative bone capacity eventually due to the lower content of growth and differentiation factors including bone morphogenetic proteins in the bone extracellular matrix (1-4).Demineralized bone matrix (DBM) 2 induces de novo bone formation when implanted into the rat muscle (5). On the contrary, DBM from OVX animals implanted into both normal and OVX rats induces only fibrous tissues suggesting that its decreased bone inducing activity is due to abnormal composition of bone from OVX rats and not to the 17␤-estradiol (E 2 )-deficient microenvironment (1). Lack of specific signals needed for ectopic bone induction may, at least in part, explain diminished bone potency to heal fractures in osteoporotic patients (6,7). It has been demonstrated that fetal osteoblastic cell lines treated by E 2 specifically express Bmp6 mRNA, whereas gene transcripts of other members of the BMP family are unaffected (8). A functional relationship between E 2 and BMP-6 was further suggested by E 2 binding to the Bmp6 gene promotor (9) and by increased BMP-6 immunostaining in bone marrow of mice treated with E 2 (10).Although numerous studies have unequivoc...

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Section: Discussionmentioning

confidence: 99%

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

Šimić

Culej

Orlić

et al. 2006

Journal of Biological Chemistry

100

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“…Cortical bone has been described in the femoral and tibial mid-diaphysis using a microcomputed tomograph. The characteristics and methods have already been described elsewhere (Lotinun et al, 2004). We used the same acquisition characteristics as for trabecular bone.…”

Section: Methodsmentioning

confidence: 99%

Dose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats

Bonnet

Laroche²,

Vico³

et al. 2006

J Pharmacol Exp Ther

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Animal studies suggest that bone remodeling is under ␤-adrenergic control via the sympathetic nervous system. The purpose of this study was to examine the preventive effect of different doses of nonspecific ␤-blockers (propranolol) on trabecular and cortical bone envelopes in ovariectomized rats. Six-month-old female Wistar rats were ovariectomized (OVX, n ϭ 60) or shamoperated (n ϭ 15). Then, OVX rats were subcutaneously injected with 0.1 (n ϭ 15), 5 (n ϭ 15), or 20 (n ϭ 15) mg/kg propranolol or vehicle (n ϭ 15) for 10 weeks. Tibial and femoral bone mineral density (BMD) were analyzed longitudinally by dual-energy X-ray absorptiometry. At death, the left tibial metaphysis and L 4 vertebrae were removed, and microcomputed tomography (Skyscan 1072; Skyscan, Aartselaar, Belgium) was performed for trabecular bone structure investigation. Histomorphometry analysis was performed on the right proximal tibia to assess bone cell activities. After 10 weeks, OVX rats had decreased BMD and trabecular parameters and increased bone turnover, as well as cortical porosity compared with the sham group (p Ͻ 0.001). Bone architecture alteration was preserved by 0.1 mg/kg propranolol due to higher trabecular number and thickness (ϩ50.35 and ϩ6.81%, respectively, than OVX; p Ͻ 0.001) and lower cortical pore number (Ϫ52.38% than OVX; p Ͻ 0.001). Animals treated by 0.1 mg/kg propranolol had a lower osteoclast surface and a higher osteoblast activity compared with OVX. Animals treated by 20 mg of propranolol did not significantly differ from OVX rats. Animals treated by 5 mg of propranolol have been partially preserved from the ovariectomy. These results showed a dose effect of ␤-blockers. The lower the dose of propranolol breeding, the better the preventive effect against ovariectomy.

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“…Mechanical strength testing was performed as previously described (Lotinun et al 2004). At sacrifice, femurs were frozen at K20 8C in normal saline.…”

Section: Mechanical Testingmentioning

confidence: 99%

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

Miller¹,

Bronk²,

Nishiyama³

et al. 2007

Journal of Endocrinology

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Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that regulates IGF bioavailability in vitro through cleavage of inhibitory IGF-binding protein-4 (IGFBP-4), has been implicated in skeletal development and injury repair responses. However, direct in vivo data are lacking. In this study, we used PAPP-A knock-out (KO) mice to determine the role of PAPP-A in fracture repair. Stabilized mid-shaft fractures were produced in femurs of 3-month-old mice. At 14 days post-fracture, complete bony bridging of the fracture callus was seen radiographically in wild-type but not in PAPP-A KO mice. Histological examination 5 to 28 days post-fracture showed reductions in the amount of intramembranous bone formation, cartilage production, endochondral ossification and remodeling in PAPP-A KO compared with wild-type mice. However, fracture healing appeared similar in both groups at 42 days post-fracture when analyzed by histology. A similar degree of healing strength in wild-type and PAPP-A KO femurs was demonstrated by mechanical testing at 28 and 42 days post-fracture. Untreated cultures of day 5 fracture calluses from wild-type mice showed robust IGFBP-4 protease activity and IGF receptor phosphorylation, whereas fracture calluses from PAPP-A KO mice had no IGFBP-4 protease activity and reduced IGF receptor phosphorylation. These data demonstrate a marked delay in fracture healing in PAPP-A KO compared with wild-type mice, and suggest that PAPP-A is necessary in the early phases of the process for expeditious fracture repair. The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response.

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Continuous Parathyroid Hormone Induces Cortical Porosity in the Rat: Effects on Bone Turnover and Mechanical Properties

Cited by 61 publications

References 33 publications

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

Dose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

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