Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

Abstract

Glucocorticoids (GC) are commonly used for the treatment of a wide variety of autoimmune, pulmonary, gastrointestinal, and malignancy conditions. One of the devastating side effects of GC use is osteoporotic fractures, particularly in the spine and hip. Bisphosphonates (BP) are the most commonly prescribed pharmacological agents for the prevention and treatment of GC‐induced osteoporosis (GIO). However, GIO is marked by reduced bone formation and BP serves mainly to decrease bone resorption. The WNT signaling pathway plays a major role in bone and mineral homeostasis. Previously, we demonstrated that overexpression of WNT16 in mice led to higher bone mineral density and improved bone microarchitecture and strength. We hypothesized that WNT16 overexpression would prevent bone loss due to glucocorticoid treatment in mice. To test our hypothesis, we treated adult wild‐type and WNT16‐transgenic mice with vehicle and GC (prednisolone; 2.1 mg/kg body weight) via slow‐release pellets for 28 days. We measured bone mass and microarchitecture by dual‐energy X‐ray absorptiometry (DXA) and micro‐CT, and performed gene expression and serum biochemical analysis. We found that GC treatment compared with the vehicle significantly decreased femoral areal bone mineral density (aBMD), bone mineral content (BMC), and cortical bone area and thickness in both wild‐type and transgenic female mice. In contrast, the trabecular bone parameters at distal femur were not significantly changed by GC treatment in male and female mice for both genotypes. Further, we observed significantly lower level of serum P1NP and a tendency of higher level of serum TRAP in wild‐type and transgenic mice due to GC treatment in both sexes. Gene expression analysis showed lower mRNA levels of Wnt16 , Opg , and Opg/Rankl ratio in GC‐treated female mice for both genotypes compared with the sex‐matched vehicle‐treated mice. These data suggest that although WNT16 overexpression resulted in higher baseline bone mineral density and bone volume per trabecular volume (BV/TV) in the transgenic mice, this was insufficient to prevent bone loss in mice due to glucocorticoid treatment. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

MicroRNA-29a Counteracts Glucocorticoid Induction of Bone Loss through Repressing TNFSF13b Modulation of Osteoclastogenesis

“…In this study, treatment with a high dose of methylprednisolone deteriorated bone mass along with significant increases in skeletal porosity and serum bone resorption markers, like TRAP5b and CTX-1. Our investigations are in agreement with other groups’ studies showing that glucocorticoid administration increased serum TRAP5b levels [28] and cortical bone loss [29]. Furthermore, miR-29a overexpression attenuated the glucocorticoid-induced osteoblast dysfunction and marrow adipose deposition [22], which is indicative that miR-29a signaling may alter osteoclast behavior in glucocorticoid-treated bone tissue.…”

Bone Strength/Bone Mass Discrepancy in Glucocorticoid‐Treated Adult Mice

“…The glucocorticoid-treated group had lower cortical bone strength both with respect to structural-dependent properties and material property estimates, regardless of the duration of treatment, paralleling data from previous investigations of these two endpoints in glucocorticoidtreated mice [16][17][18]. Others reported a glucocorticoid-related difference in cortical bone mass only without reporting cortical bone strength data [20,[22][23][24][25].…”

“…Others reported a glucocorticoid-related difference in cortical bone mass only without reporting cortical bone strength data [20,[22][23][24][25]. On the other hand, there was no glucocorticoid effect on either ultimate compressive stress or trabecular bone volume in the sixth lumbar vertebral body or trabecular bone volume in the distal femoral metaphysis at Day 60 of treatment, as reported previously [16,26]. However, others have reported significantly lower trabecular bone mass with glucocorticoid treatment in this timeframe [17-19, 21-26, 28-29, 31-34].…”

“…Most indices of cortical bone strength displayed a negative effect of glucocorticoid treatment by Day 60 that did not worsen by Day 120. A few studies have noted that glucocorticoid-related differences in cortical bone strength in mice emerge as early as 28 days[16][17][18]. Because our earliest time point was Day 60, our data leave open the possibility that the glucocorticoid-related differences in cortical bone strength plateau as early as 28 days of treatment.…”

Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish

“…(15,16) However, one study showed that Wnt16 overexpression in osteoblasts could not counter glucocorticoid-induced osteoporosis and bone loss, suggesting that other factors play a role. (16) One possible explanation could include interactions with the immune system. Glucocorticoid treatment in zebrafish has been shown to suppress the innate immune system and osteoblast activity, leading to decreased bone synthesis.…”