Hong AR, et al. Endocrinol Metab. 2018 Dec;33(4):435-444. https://doi.org/10.3803/EnM.2018.33.4.435

Intermittent administration of parathyroid hormone (PTH) increases bone mass, at least in part, by increasing the number of osteoblasts. One possible source of osteoblasts might be conversion of inactive lining cells to osteoblasts, and indirect evidence is consistent with this hypothesis. To better understand the possible effect of PTH on lining cell activation, a lineage tracing study was conducted using an inducible gene system. Dmp1‐CreERt2 mice were crossed with ROSA26R reporter mice to render targeted mature osteoblasts and their descendents, lining cells and osteocytes, detectable by 5‐bromo‐4‐chloro‐3‐indolyl‐β‐d‐galactopyranoside (X‐gal) staining. Dmp1‐CreERt2(+):ROSA26R mice were injected with 0.25 mg 4‐OH‐tamoxifen (4‐OHTam) on postnatal days 3, 5, 7, 14, and 21. The animals were euthanized on postnatal day 23, 33, or 43 (2, 12, or 22 days after the last 4‐OHTam injection). On day 43, mice were challenged with a subcutaneous injection of human PTH (1–34, 80 µg/kg) or vehicle once daily for 3 days. By 22 days after the last 4‐OHTam injection, most X‐gal (+) cells on the periosteal surfaces of the calvaria and the tibia were flat. Moreover, bone formation rate and collagen I(α1) mRNA expression were decreased at day 43 compared to day 23. After 3 days of PTH injections, the thickness of X‐gal (+) cells increased, as did their expression of osteocalcin and collagen I(α1) mRNA. Electron microscopy revealed X‐gal–associated chromogen particles in thin cells prior to PTH administration and in cuboidal cells following PTH administration. These data support the hypothesis that intermittent PTH treatment can increase osteoblast number by converting lining cells to mature osteoblasts in vivo. © 2012 American Society for Bone and Mineral Research.

Mesenchymal cells are able to differentiate into several distinct cell types, including osteoblasts and adipocytes. The commitment to a particular lineage may be regulated by specific transcription factors. Peroxisome proliferator-activated receptor-γ (PPARγ), acting in conjunction with CCAAT/enhancer-binding protein-α, has been suggested as a key regulator of adipogenic differentiation. Previous studies have shown that the activation of PPARγ in osteoblasts suppresses osteoblast differentiation and the expression of osteocalcin, an osteoblast-specific protein. However, the mechanism of this inhibition remains unclear. We investigated the effect of PPARγ activation on the expression of osteocalcin and analyzed the molecular mechanism. Mouse osteoblastic MC3T3-E1 cells expressed PPARγ, which was transcriptionally active, whereas rat osteosarcoma ROS 17/2.8 cells did not. Treatment of MC3T3-E1 osteoblasts and ROS 17/2.8 cells stably transfected with PPARγ2 with the PPARγ activator 15-deoxy-Δ^12,14-prostaglandin J₂ inhibited the mRNA expression of osteocalcin and Runx2, the latter of which is a key transcription factor in osteoblast differentiation. This decreased expression of osteocalcin and Runx2 was partly explained by the decreased level of Runx2 resulting from the suppressed transcription from the Runx2 promoter. However, in addition to this indirect effect, the activation of PPARγ by 15-deoxy-Δ^12,14-prostaglandin J₂ directly suppressed the Runx2-mediated induction of the activities of the osteocalcin promoter and the artificial promoter p6OSE2, which contains six tandem copies of osteoblast-specific element-2, the Runx2-binding promoter sequence. This inhibition was mediated by a physical interaction between PPARγ and Runx2 and the subsequent repression of the transcriptional activity at the osteoblast-specific element-2 sequence. Thus, this study demonstrates that the activation of PPARγ inhibits osteocalcin expression both by suppressing the expression of Runx2 and by interfering with the transactivation ability of Runx2.

Trabecular bone score (TBS) is a novel texture index that evaluates the pixel gray-level variations in lumbar spine dual-energy X-ray absorptiometry images and is related to bone microarchitecture independent of bone mineral density (BMD). We investigated lumbar spine TBS as an indicator for skeletal deterioration in diabetes. Cross-sectional data were collected from subjects participating in an ongoing prospective, community-based, cohort study from 2009 to 2010. We included 1229 men and 1529 postmenopausal women older than 50 years in the Ansung cohort. Biochemical parameters, lumbar spine TBS, and BMD from dual-energy X-ray absorptiometry images were measured. Lumbar spine TBS was lower in men with diabetes than in nondiabetic men (1.287 ± 0.005 vs 1.316 ± 0.003, P < .001), whereas lumbar spine BMD was higher in men with diabetes (1.135 ± 0.010 vs 1.088 ± 0.006 g/cm(2)). Lumbar spine TBS was lower in women with diabetes than in nondiabetic women only in an unadjusted model (1.333 ± 0.004 vs 1.353 ± 0.003). However, women younger than 65 years (n = 707) with diabetes had a lower TBS than those without diabetes, even after adjusted for covariates (P < .001). Diabetes was not associated with BMD at femur sites in both genders. TBS was negatively correlated with glycated hemoglobin, fasting plasma glucose, fasting insulin, and homeostasis model assessment for insulin resistance but not with homeostasis model assessment for β-cell function in both genders. The inverse association between lumbar spine TBS and insulin resistance may make it an indicator for determining skeletal deterioration in diabetic patients who have high BMD.