anabolic

Lactate Mediates the Bone Anabolic Effect of High-Intensity Interval Training by Inducing Osteoblast Differentiation

AUTHORS

Zhu, Zhenglin; Chen, Yi; Zou, Jing; Gao, Shengqiang; Wu, Dandong; Li, Xuelun; Hu, Ning; Zhao, Jinzhong; Huang, Wei; Chen, Hong

ABSTRACT

Background:

High-intensity interval training (HIIT) reportedly improves bone metabolism and increases bone mineral density (BMD). The purpose of the present study was to investigate whether lactate mediates the beneficial effects of exercise on BMD, bone microarchitecture, and biomechanical properties in an established osteoporotic animal model. In addition, we hypothesized that lactate-induced bone augmentation is achieved through enhanced osteoblast differentiation and mineralization.

Methods:

A total of 50 female C57BL/6 mice were randomly allocated into 5 groups: the nonovariectomized group, the ovariectomized group (OVX), the HIIT group (OVX + HIIT), the HIIT with lactate transporter inhibition group (OVX + HIIT + INH), and the lactate subcutaneous injection group (OVX + LAC). After 7 weeks of intervention, bone mass, bone strength, and bone formation/resorption processes were evaluated via microcomputed tomography (micro-CT), biomechanical testing, histological analysis, and serum biochemical assays; in vitro studies were performed to explore the bone anabolic effect of lactate at the cellular level.

Results:

Micro-CT revealed significantly increased BMD in both the OVX + HIIT group (mean difference, 41.03 mg hydroxyapatite [HA]/cm3 [95% CI, 2.51 to 79.54 mg HA/cm3]; p = 0.029) and the OVX + LAC group (mean difference, 40.40 mg HA/cm3 [95% CI, 4.08 to 76.71 mg HA/cm3]; p = 0.031) compared with the OVX group. Biomechanical testing demonstrated significantly improved mechanical properties in those 2 groups. However, the beneficial effects of exercise on bone microstructure and biomechanics were largely abolished by blocking the lactate transporter. Notably, histological and biochemical results indicated that increased bone formation was responsible for the bone augmentation effects of HIIT and lactate. Cell culture studies showed a marked increase in the expression of osteoblastic markers with lactate treatment, which could be eliminated by blocking the lactate transporter.

Conclusions:

Lactate may have mediated the bone anabolic effect of HIIT in osteoporotic mice, which may have resulted from enhanced osteoblast differentiation and mineralization.

Clinical Relevance:

Lactate may mediate the bone anabolic effect of HIIT and serve as a potential inexpensive therapeutic strategy for bone augmentation.

Sex-specific differences in Gsα-mediated signaling downstream of PTH1R activation by abaloparatide in bone

AUTHORS

Srilatha Swami, Joshua Johnson, Lawrence Vecchi, Matthew Kim, Beate Lanske, Rachelle Johnson, Joy Wu

ABSTRACT

Teriparatide, recombinant parathyroid hormone (PTH[1-34]), and abaloparatide, an analogue of PTH related-peptide (PTHrP[1-34]), are both anabolic medications for osteoporosis that target the PTH receptor PTH1R. PTH1R is a G protein-coupled receptor, and the stimulatory Gs protein is an important mediator of the anabolic actions of PTH1R activation in bone. We have published that mice lacking the α subunit of Gs in osteoprogenitors do not increase bone mass in response to PTH[1-34]. Unexpectedly, however, PTH[1-34] still increases osteoblast numbers and bone formation rate in male mice, suggesting that PTH1R may have both Gs-dependent and independent actions in bone. Here we examine the role of Gs signaling in the anabolic actions of abaloparatide. We find that abaloparatide increases bone formation in male mice with postnatal deletion of Gsα in Osx-expressing osteoprogenitors (P-GsαOsxKO mice), but not in female P-GsαOsxKO mice. Therefore, abaloparatide has anabolic effects on bone in male but not female mice that appear to be independent of Gs-mediated signaling.

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Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading

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Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β-catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl-Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl-Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl-Ab therapy.

Interleukin-32 Gamma Stimulates Bone Formation by Increasing miR-29a in Osteoblastic Cells and Prevents the Development of Osteoporosis

Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear.

Increased Bone Mass in Female Mice Lacking Mast Cell Chymase

Here we addressed the potential impact of chymase, a mast-cell restricted protease, on mouse bone phenotype. We show that female mice lacking the chymase Mcpt4 acquired a persistent expansion of diaphyseal bone in comparison with wild type controls, reaching a 15% larger diaphyseal cross sectional area at 12 months of age.

FIAT deletion increases bone mass but does not prevent high-fat-diet-induced metabolic complications

FIAT (Factor Inhibiting ATF4-mediated Transcription) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat-/Y) at 8 and 16 weeks of age. Fiat-/Y mice appeared normal at birth and weight gain was comparable between genotypes. μCT analysis of proximal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat-/Y mice.