Disruption of BMP Signaling Prevents Hyperthyroidism-Induced Bone Loss in Male Mice

Abstract

Thyroid hormones (TH) are key regulators of bone health, and TH excess in mice causes high bone turnover-mediated bone loss. However, the underlying molecular mechanisms of TH actions on bone remain poorly defined. Here, we tested the hypothesis whether TH mediate their effects via the pro-osteogenic bone morphogenetic protein (BMP) signaling pathway in vitro and in vivo. Primary murine osteoblasts treated with 3,3 0 ,5-triiodo-L-thyronine (T 3) showed an enhanced differentiation potential, which was associated with activated canonical BMP/SMAD signaling reflected by SMAD1/5/8 phosphorylation. Blocking BMP signaling at the receptor (LDN193189) and ligand level (noggin, anti-BMP2/BMP4 neutralizing antibodies) inhibited T 3-induced osteogenic differentiation. In vivo, TH excess over 4 weeks in male C57BL/6JRj mice led to severe trabecular bone loss with a high bone turnover that was completely prevented by treatment with the BMP ligand scavenger ALK3-Fc. Thus, TH activate the canonical BMP pathway in osteoblasts to promote their differentiation and function. Importantly, this study indicates that blocking the BMP pathway may be an effective strategy to treat hyperthyroidism-induced bone loss.

Vitamin D inhibits bone loss in mice with thyrotoxicosis by activating the OPG/RANKL and Wnt/β-catenin signaling pathways

“…This finding indicated that bone resorption in the mice with thyrotoxicosis increased significantly, and supplementation with vitamin D reduced the number of osteoclasts in these mice. In addition, the micro-CT results showed that the BMD of the lumbar vertebrae and femur in the mice with thyrotoxicosis decreased and the bone architecture was destroyed, which was similar to the findings of most studies ( 18 , 19 ). Treatment with vitamin D significantly improved the BMD and trabecular bone architecture of the lumbar vertebrae and femur in the mice with low LT4-induced thyrotoxicosis.…”

The Bone Morphogenetic Protein Pathway: The Osteoclastic Perspective

“…According to this, the BMP antagonist noggin ameliorated osteoclast formation through its effects on stromal cell/osteoblast differentiation (Abe et al, 2010). Recently, we demonstrated reduced osteoclast numbers in mice treated over 4 weeks with ALK3-Fc, a recombinant fusion protein that specifically scavenges BMPR1A/ALK3-activating BMP ligands (Lademann et al, 2020). However, due to systemic drug application it is unclear whether osteoclasts are affected in a direct or indirect manner as ALK3-Fc is reported to enhance OPG and reduce RANKL levels in serum of treated mice as well as in SaOS2 cells (Baud'huin et al, 2012).…”

Endocrine Regulation on Bone by Thyroid

“…The expression of differentiation markers was increased, and Smad1/5/8 phosphorylation was mediated by BMP signaling when osteoblasts were treated with T3. This finding suggested that THs could promote osteoblast differentiation via the BMP/Smad signaling pathway ( 44 ). C2C12 myoblasts were transfected with a BMP/Smad-specific reporter construct and treated with Bmp2 or Wnt3a ligands, and the results showed that not only Bmp2 but also Wnt3a enhanced BMP/Smad activity.…”

“…Therefore, sclerostin may be a potential therapeutic target in hyperthyroidism related osteoporosis ( 68 ). On the other hand, excessive activation of BMP and Wnt pathway were observed in hyperthyroidism, indicating that BMP or Wnt pathway may be other therapeutic targets for hyperthyroidism-induced bone loss ( 44 , 69 ).…”