Bone Mineral Remodeling Research Articles

Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density.

Temporal and spatial variations in bone marrow adipose tissue (MAT) can be indicative of several pathologies and confound current methods of assessing immediate changes in bone mineral remodeling. We present a novel dual-energy computed tomography (DECT) method to monitor MAT and marrow-corrected volumetric BMD (mcvBMD) throughout the body. Twenty-three cancellous skeletal sites in 20 adult female cadavers aged 40-80years old were measured using DECT (80 and 140kVp). vBMD was simultaneous recorded using QCT. MAT was further sampled using MRI. Thirteen lumbar vertebrae were then excised from the MRI-imaged donors and examined by microCT. After MAT correction throughout the skeleton, significant differences (p<0.05) were found between QCT-derived vBMD and DECT-derived mcvBMD results. McvBMD was highly heterogeneous with a maximum at the posterior skull and minimum in the proximal humerus (574 and 0.7mg/cc, respectively). BV/TV and BMC have a nearly significant correlation with mcvBMD (r=0.545, p=0.057 and r=0.539, p=0.061, respectively). MAT assessed by DECT showed a significant correlation with MRI MAT results (r=0.881, p<0.0001). Both DECT- and MRI-derived MAT had a significant influence on uncorrected vBMD (r=-0.86 and r=-0.818, p≤0.0001, respectively). Conversely, mcvBMD had no correlation with DECT- or MRI-derived MAT (r=0.261 and r=0.067). DECT can be used to assess MAT while simultaneously collecting mcvBMD values at each skeletal site. MAT is heterogeneous throughout the skeleton, highly variable, and should be accounted for in longitudinal mcvBMD studies. McvBMD accurately reflects the calcified tissue in cancellous bone.

The β-Adrenergic System and Bone Mineral Remodeling

Known bone functions include maintaining the homeostasis of the calcium–phosphate metabolism, repairing damage produced by daily exercise and maintaining the bone architecture according to mechanical requirements, meaning that bone remodeling is a true homeostatic function. Bone is a dynamic tissue that is constantly changing through bone remodeling, which requires a lot of energy. The sympathetic nervous system contributes to bone remodeling and is one form of interaction between the skeleton and the brain, through leptin, an adipocyte-derived hormone, which uses this route to induce expression of the gene for the receptor activator of nuclear factor kappa-β ligand, an osteoclast differentiation factor. This review summarizes basic research findings on the role of the sympathetic nervous system in bone metabolism.

The Influence of Therapeutic Radiation on the Patterns of Bone Remodeling in Ovary-Intact and Ovariectomized Mice

Our purpose was to characterize changes in bone remodeling associated with localized radiation that models therapeutic cancer treatment in ovary-intact (I) and ovariectomized (OVX) mice and to evaluate the influence of radiation on the pattern of bone mineral remodeling. Young adult, female BALB/c mice, I and OVX, were used (n = 71). All mice were intravenously injected with 15 μCi (45)Ca. Thirty days post-(45)Ca administration, the hind limbs of 17 mice were exposed to a single dose of 16 Gy radiation (R). The time course of (45)Ca excretion, serum CTx and osteocalcin markers, and cancellous bone volume fraction (BV/TV) and cortical thickness (Ct.Th) of the distal femur were assayed. Cellular activity and dynamic histomorphometry were performed. Irradiation resulted in rapid increases in fecal (45)Ca excretion compared to control groups, indicating increased bone remodeling. CTx increased rapidly after irradiation, followed by an increase in osteocalcin concentration. BV/TV decreased in the I mice following irradiation. Ct.Th increased in the OVX groups following irradiation. I+R mice exhibited diminished osteoblast surface, osteoclast number, and mineral apposition. Our murine model showed the systemic effects (via (45)Ca excretion) and local effects (via bone microarchitecture and surface activity) of clinically relevant, therapeutic radiation exposure. The I and OVX murine models have similar (45)Ca excretion but different bone microarchitectural responses. The (45)Ca assay effectively indicates the onset and rate of systemic bone mineral remodeling, providing real-time assessment of changes in bone histomorphometric parameters. Monitoring bone health via a bone mineral marker may help to identify the appropriate time for clinical intervention to preserve skeletal integrity.

Molecular Mechanisms of Vitamin D Action

The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP(9k), and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.

Skeletal Remodeling Following Clinically Relevant Radiation-Induced Bone Damage Treated with Zoledronic Acid

Our aim was to determine if zoledronic acid (ZA) changes (45)Ca pharmacokinetics and bone microstructure in irradiated, ovary-intact (I) and irradiated, ovariectomized mice (OVX), two groups with different patterns of skeletal damage. The hind limbs of I and OVX BALB/c mice received a single 16-Gy radiation dose, simulating pre- and postmenopausal female cancer patients undergoing radiation treatment. All I and OVX mice were radiolabeled with 15μCi (45)Ca. Mice were treated with or without a 0.5mg/kg injection of ZA. The time course of bone mineral remodeling was evaluated using a fecal (45)Ca assay, measured by liquid scintillation. A group of nonirradiated, intact mice were used for the longitudinal evaluation of (45)Ca biodistribution. Distal femur bone histomorphometric parameters were measured using microCT at 50days post-ZA intervention. Most (45)Ca was incorporated into the skeleton and eliminated from the soft tissues within 3-5days postirradiation, attaining a steady state of excretion at 25-30days. ZA intervention in both groups resulted in a rapid decrease in fecal (45)Ca excretion. There was a significant difference in (45)Ca excretion in the OVX±ZA (P=0.005) group but not in the I±ZA (P=0.655) group. The rate of excretion of fecal (45)Ca was slower in the OVX+ZA compared to the I+ZA group (P=0.064). (45)Ca assay is useful to monitor the time course of bone mineral remodeling after an antiresorptive intervention in irradiated mice, providing a basis to investigate bone effects of cancer therapy protocols. For equivalent doses of ZA, recovery may depend on the nature and degree of skeletal damage.

Effect of Salinity on Hydroxyapatite Dissolution Studied by Atomic Force Microscopy

The complexity of bone tissue and the lack of techniques for directly probing bone surfaces in vivo have hindered studies on the fundamental mechanisms of bone mineral remodeling. Here, we addressed these issues by using single crystal hydroxyapatite (HAP) as a well-defined bone surface model and directly observe its surface using in situ atomic force microscopy. Specifically, we investigated the effects of NaCl concentration on the dissolution of HAP (100) surfaces and found that NaCl strongly suppressed HAP dissolution kinetics, including at physiological ion concentrations. These findings indicate that local ion concentrations in vivo may contribute significantly to the stability of bone mineral. Moreover, our analysis of HAP surfaces over a broad range of pH conditions suggests that only one kind of surface termination exists exclusively in the solutions we used. This observation is important for understanding the surface chemistry of HAP. Our molecular level, real-time observations of HAP dissolution...

Defect Induced Asymmetric Pit Formation on Hydroxyapatite

Defect sites on bone minerals play a critical role in bone remodeling processes. We investigated single crystal hydroxyapatite (100) surfaces bearing crystal defects under acidic dissolution conditions using real-time in situ atomic force microscopy. At defect sites, surface structure-dependent asymmetric hexagonal etch pits were formed, which dominated the overall dissolution rate. Meanwhile, dissolution from the flat terraces proceeded by stochastic formation of flat bottom etch pits. The resulting pit shapes were intrinsically dictated by the HAP crystal structure. Computational modeling also predicted different step energies associated with different facets of the asymmetric etch pits. Our microscopic observations of HAP dissolution are significant for understanding the effects of local surface structure on the bone mineral remodeling process and provide useful insights for the design of novel therapies for treating osteoporosis and dental caries.