Mice Lacking Bone Sialoprotein (BSP) Lose Bone after Ovariectomy and Display Skeletal Site-Specific Response to Intermittent PTH Treatment

Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP−/−) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP+/+) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP+/+ and BSP−/− mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP−/− mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP+/+ but not BSP−/− mice. PTH increased cortical thickness and bone area in BSP+/+ but not BSP−/− mice and stimulated the bone formation rate specifically in the endosteum of BSP+/+ mice and the periosteum of BSP−/− mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP−/− mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP−/− mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in compensating for the absence of BSP.

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Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00111.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1406-E1417 ◽

Cited By ~ 13

Author(s):

Kanogwun Thongchote ◽

Saovaros Svasti ◽

Jarinthorn Teerapornpuntakit ◽

Nateetip Krishnamra ◽

Narattaphol Charoenphandhu

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Trabecular Bone ◽

Elevated Serum ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Mineral Density ◽

Trabecular Thickness ◽

Running Exercise

A marked decrease in β-globin production led to β-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous β-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1–2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1α and -1β. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in β-thalassemia.

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Bone health in spacefaring rodents and primates: systematic review and meta-analysis

npj Microgravity ◽

10.1038/s41526-021-00147-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jingyan Fu ◽

Matthew Goldsmith ◽

Sequoia D. Crooks ◽

Sean F. Condon ◽

Martin Morris ◽

...

Keyword(s):

Bone Formation ◽

Trabecular Bone ◽

Bone Health ◽

Volume Fraction ◽

Meta Analysis ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Bone Volume Fraction ◽

Percentage Difference ◽

Induced Changes

AbstractAnimals in space exploration studies serve both as a model for human physiology and as a means to understand the physiological effects of microgravity. To quantify the microgravity-induced changes to bone health in animals, we systematically searched Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. We selected 40 papers focusing on the bone health of 95 rats, 61 mice, and 9 rhesus monkeys from 22 space missions. The percentage difference from ground control in rodents was –24.1% [Confidence interval: −43.4, −4.9] for trabecular bone volume fraction and –5.9% [−8.0, −3.8] for the cortical area. In primates, trabecular bone volume fraction was lower by –25.2% [−35.6, −14.7] in spaceflight animals compared to GC. Bone formation indices in rodent trabecular and cortical bone were significantly lower in microgravity. In contrast, osteoclast numbers were not affected in rats and were variably affected in mice. Thus, microgravity induces bone deficits in rodents and primates likely through the suppression of bone formation.

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Prolyl Hydroxylase Domain-Containing Protein 3 Gene Expression in Chondrocytes Is Not Essential for Bone Development in Mice

Cells ◽

10.3390/cells10092200 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2200

Author(s):

Weirong Xing ◽

Sheila Pourteymoor ◽

Gustavo A. Gomez ◽

Yian Chen ◽

Subburaman Mohan

Keyword(s):

Gene Expression ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Bone Volume ◽

Endochondral Bone Formation ◽

Chondrocyte Differentiation ◽

Trabecular Bone Volume ◽

Endochondral Bone ◽

Trabecular Bone Mass

We previously showed that conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of Phd2 gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in Phd3 expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the Phd3 gene in chondrocytes by crossing Phd3 floxed (Phd3flox/flox) mice with Col2α1-Cre mice. Loss of Phd3 expression in the chondrocytes of Cre+; Phd3flox/flox conditional knockout (cKO) mice was confirmed by real time PCR. At 16 weeks of age, neither body weight nor body length was significantly different in the Phd3 cKO mice compared to Cre−; Phd3flox/flox wild-type (WT) mice. Areal BMD measurements of total body as well as femur, tibia, and lumbar skeletal sites were not significantly different between the cKO and WT mice at 16 weeks of age. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype difference was found for any of the trabecular bone measurements of either the femur or the tibia. Trabecular bone volume of distal femur epiphysis was not different between cKO and WT mice. Histology analyses revealed Phd3 cKO mice exhibited a comparable chondrocyte differentiation and proliferation, as evidenced by no changes in cartilage thickness and area in the cKO mice as compared to WT littermates. Consistent with the in vivo data, lentiviral shRNA-mediated knockdown of Phd3 expression in chondrocytes did not affect the expression of markers of chondrocyte differentiation (Col2, Col10, Acan, Sox9). Our study found that Phd2 but not Phd3 expressed in chondrocytes regulates endochondral bone formation, and the compensatory increase in Phd3 expression in the chondrocytes of Phd2 cKO mice is not the cause for increased trabecular bone mass in Phd2 cKO mice.

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Bone Formation and Resorption as the Determinants of Trabecular Bone Volume in Normal and Osteoporotic Men

Scottish Medical Journal ◽

10.1177/003693308402900307 ◽

1984 ◽

Vol 29 (3) ◽

pp. 171-175 ◽

Cited By ~ 16

Author(s):

B. E. C. Nordin ◽

J. Aaron ◽

R. Speed ◽

R. M. Francis ◽

N. Makins

Keyword(s):

Bone Formation ◽

Trabecular Bone ◽

Inverse Function ◽

Positive Function ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Age Related ◽

Osteoporosis In Men ◽

Spinal Osteoporosis ◽

The Mean

Trabecular bone volume, forming surface and percent surface resorption have been determined in iliac crest samples obtained post mortem from 43 young men and 49 elderly men and in biopsies obtained from 22 males with spinal osteoporosis. The mean bone volume was significantly lower in the old than in the young controls and significantly lower again in the osteoporotic cases. Forming surfaces were significantly lower in the old than the young controls but were not different as between old controls and cases of osteoporosis. Percent surface resorption was the same in young and old controls but significantly increased in the osteoporotics. Multiple regression analysis showed that trabecular bone volume was a significant positive function of forming surface and a significant inverse function of fractional surface resorption. Age-related (simple) osteoporosis in men appears to be due to reduced bone formation whereas pathological (accelerated) osteoporosis is due to increased bone resorption.

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Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Journal of Biological Chemistry ◽

10.1074/jbc.m115.679753 ◽

2015 ◽

Vol 291 (4) ◽

pp. 1631-1642 ◽

Cited By ~ 23

Author(s):

Partha Sinha ◽

Piia Aarnisalo ◽

Rhiannon Chubb ◽

Ingrid J. Poulton ◽

Jun Guo ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Phospholipase C ◽

Osteoblast Differentiation ◽

Bone Volume ◽

Trabecular Bone Volume ◽

Male And Female ◽

Osteoblast Lineage

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-GsαOsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1–34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-GsαOsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-GsαOsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.

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The effect of zoledronate on bone remodeling during the healing process

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502007000200007 ◽

2007 ◽

Vol 22 (2) ◽

pp. 115-119 ◽

Cited By ~ 11

Author(s):

Marcos Almeida Matos ◽

Francisco Pereira Araújo ◽

Fábio Brasileiro Paixão

Keyword(s):

Trabecular Bone ◽

Bone Remodeling ◽

Healing Process ◽

Bone Volume ◽

Control Group ◽

Distilled Water ◽

Trabecular Bone Volume ◽

Tissue Volume ◽

Group A ◽

Experimental Group

PURPOSE: To check the effect of zoledronate in bone remodeling during bone healing. METHODS: Thirty rabbits were divided into two groups of fifteen animals each (control and experimental group respectively). Shaft osteotomy was performed on the cranial portion of the fibula of each animal. In the experimental group, a single dose of 0.04mg/kg of zoledronate was administered. In the control group, the same volume of bi-distilled water was administered. After one, two and four weeks, animals of both groups were killed and histological sections of the fibular metaphyseal area were examined histomorphometrically. The parameters analyzed were tissue volume (TV), fractional trabecular bone volume (BV/TV) and fractional medullary fibrous volume (FbV/TV). RESULTS: Tissue volume increased in the experimental group (237.2mm².10-2) compared to the control (166.62mm².10-2). Trabecular bone volume was significantly larger in the experimental (60.2%) than in the control group (34.8%).The amount of fibrosis volume decreased in the experimental group (22%) compared to the control (49.4%). CONCLUSION: The effect of zoledronate is characterized by accentuated stimulus of bone formation in the metaphyseal area, resulting in a larger amount of trabecular bone volume and little fibrosis volume.

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The anabolic effect of 17β-oestradiol on the trabecular bone of adult rats is suppressed by indomethacin

Journal of Endocrinology ◽

10.1677/joe.0.1330189 ◽

1992 ◽

Vol 133 (2) ◽

pp. 189-195 ◽

Cited By ~ 7

Author(s):

J. W. M. Chow ◽

J. M. Lean ◽

T. Abe ◽

T. J. Chambers

Keyword(s):

Bone Formation ◽

Trabecular Bone ◽

Bone Growth ◽

Formation Rate ◽

Bone Volume ◽

Female Rats ◽

Mineral Apposition Rate ◽

Adult Rats ◽

Bone Formation Rate

ABSTRACT We have previously demonstrated that administration of oestrogen, at doses sufficient to raise serum concentrations to those seen in late pregnancy, increases trabecular bone formation in the metaphysis of adult rats. To determine whether prostaglandins (PGs), which have been shown to induce osteogenesis in vivo, play a role in the induction of bone formation by oestrogen, 13-week-old female rats were given daily doses of 4 mg 17β-oestradiol (OE2)/kg for 17 days, alone or with indomethacin (1 mg/kg). The rats were also given double fluorochrome labels and at the end of the experiment tibias were subjected to histomorphometric assessment. Treatment with OE2 suppressed longitudinal bone growth and increased uterine wet weight, as expected, and neither response was affected by indomethacin. Oestrogen also induced a threefold increase in trabecular bone formation in the proximal tibial metaphysis, which resulted in a substantial increase in trabecular bone volume. As previously observed, the increase in bone formation was predominantly due to an increase in osteoblast recruitment (as judged by an increase in the percentage of bone surface showing double fluorochrome labels), with only a minor increase in the activity of mature osteoblasts (as judged by the mineral apposition rate). Indomethacin abolished the increase in osteoblastic recruitment, but the activity of mature osteoblastic cells remained high. The bone formation rate and bone volume remained similar to controls. The results suggest that PG production may be necessary for the increased osteoblastic recruitment induced by oestrogen, but not to mediate the effects of oestrogen on the activity of mature osteoblasts. Journal of Endocrinology (1992) 133, 189–195

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Effect of Minocycline on Osteoporosis

Advances in Dental Research ◽

10.1177/08959374980120012401 ◽

1998 ◽

Vol 12 (1) ◽

pp. 71-75 ◽

Cited By ~ 17

Author(s):

S. Williams ◽

A. Wakisaka ◽

Q.Q. Zeng ◽

J. Barnes ◽

S. Seyedin ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Trabecular Bone ◽

Formation Rate ◽

Inhibitory Effect ◽

Mineral Apposition Rate ◽

Mineral Density ◽

Bone Formation Rate ◽

Trabecular Thickness ◽

Trabecular Bone Area

The effect of oral minocycline on osteopenia in ovariectomized (OVX) old rats was examined in this study. Rats were divided into 4 groups: sham-operated, OVX followed by treatment with vehicle, minocycline, or 17β-estradiol. The treatment was initiated one day after OVX and proceeded for 8 wks. OVX reduced bone mineral density (BMD) in the whole femur and in the femoral regions that are enriched in trabecular bone. Treatment with minocycline or estrogen prevented a decrease in BMD. Femoral trabecular bone area, trabecular number, and trabecular thickness were reduced, and trabecular separation was increased by OVX. Treatment with minocycline or estrogen abolished the detrimental effects induced by OVX. OVX also reduced indices that reflect the interconnectivity of trabecular bone, and the loss of trabecular connectivity was prevented by treatment with minocycline or estrogen. Based on the levels of urinary pyridinoline, we showed that the effect of estrogen, but not minocycline, was primarily through its inhibitory effect on bone resorption. Analysis of bone turnover activity suggests that OVX increased parameters associated with bone resorption (eroded surface) and formation (osteoid surface, mineralizing surface, mineral apposition rate, and bone formation rate). Treatment with minocycline reduced bone resorption modestly and stimulated bone formation substantially. In contrast, treatment with estrogen drastically reduced parameters associated with both bone resorption and formation. We have concluded that oral minocycline can effectively prevent the decrease in BMD and trabecular bone through its dual effects on bone resorption and formation.

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The Incorporation of Platelet-rich Plasma into Calcium Phosphate Cement Enhances Bone Regeneration in Osteoporosis

January 2018 - Pain Physician ◽

10.36076/ppj.2014/17/e737 ◽

2014 ◽

Vol 6;17 (6;12) ◽

pp. E737-E745

Author(s):

Kyung-Hoon Kim

Keyword(s):

Bone Regeneration ◽

Trabecular Bone ◽

Volume Fraction ◽

Platelet Rich Plasma ◽

Bone Volume ◽

Filler Materials ◽

Trabecular Bone Volume ◽

Mineral Density ◽

Bone Volume Fraction ◽

Trabecular Thickness

Background: Polymethyl methacrylate (PMMA) bone cement is widely used for osteoplasty. However, previous studies have demonstrated the adverse effects of PMMA due to its excessive stiffness and heat production. Recently, calcium phosphate cement (CPC) that overcomes those negative effects has been successfully applied in osteoplasty. The potential problem of CPC is markedly less initial stiffness. It leads to progressive, repeated collapse in the treated vertebra before CPC has been replaced by new bone that would provide substantial improvement in compressive strength and stiffness. The activated platelets in platelet-rich plasma (PRP) release a high concentration of growth factors which play an important role in bone healing. Objective: To investigate whether PRP could accelerate the osteoconduction of CPC and enhance the bone strength of the treated vertebra in an animal model. Study Design: Controlled animal study. Setting: Laboratory animal study, Methods: Thirty-two female Sprague-Dawley rats were ovariectomized at 8 weeks of age. After 3 months, they were randomly divided into 4 groups and received cement augmentation in the fifth caudal spine with different filler materials; sham-operated rats (S), PMMA (P), CPC (C), and CPC + PRP (CP). Bone mineral density (BMD) and trabecular type-associated morphological parameters, including trabecular bone volume fraction and trabecular thickness in the augmented caudal spine, were evaluated by micro-computed tomography (mirco-CT) 2 weeks after the cementoplasty. Histological analysis was also performed to compare the bone regeneration. Results: The trabecular bone volume fraction in the CP group was significantly greater than those of all the other groups. Trabecular thickness was higher in the CP group than the S and P groups. This augmented trabecular structure in the CP group accordingly showed higher BMD. Histological evaluations showed significantly more bone regeneration in the CP group. Limitations: There has been a concern that the effect of PRP would be dependent on the species, and might show different results in humans. Baseline values of micro-CT analysis were not measured, which could have provided exact evidence of the changes in trabecular microarchitecture parameters and cement resorption profiles. Finally, caudal vertebrae with filler materials used in biological study should have been compared by their mechanical properties using biomechanical evaluations for a more coherent study, which was not possible due to technical problems. Conclusions: Incorporating PRP into CPC could accelerate osteoconduction in the augmented vertebra leading to improvement of trabecular bone microarchitecture and BMD in rats. Key words: Bone mineral density, calcium phosphates, cementoplasty, histology, osteoconduction, osteoporosis, platelet-rich plasma, polymethyl methacrylate, vertebra

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