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Updated: May 31, 2026
Effect of Anti-c-fms Antibody on Osteoclast Formation and Proliferation of Osteoclast Precursor In Vitro
Published on: March 18, 2019
The influence of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on
Risheng Ma1, Syed Morshed, Rauf Latif
1Thyroid Research Unit, Mount Sinai School of Medicine and James J Peters Veterans Affairs Medical Center, New York, New York 10468, USA. risheng.ma@mssm.edu
Background:
We have shown that thyroid-stimulating hormone (TSH) has a direct inhibitory effect on osteoclastic bone resorption and that TSH receptor (TSHR) null mice display osteoporosis. To determine the stage of osteoclast development at which TSH may exert its effect, we examined the influence of TSH and agonist TSHR antibodies (TSHR-Ab) on osteoclast differentiation from murine embryonic stem (ES) cells to gain insight into bone remodeling in hyperthyroid Graves' disease.
Methods:
Osteoclast differentiation was initiated in murine ES cell cultures through exposure to macrophage colony stimulation factor, receptor activator of nuclear factor кB ligand, vitamin D, and dexamethasone.
Results:
Tartrate resistant acid phosphatase (TRAP)-positive osteoclasts formed in ~12 days. This coincided with the expected downregulation of known markers of self renewal and pluripotency (including Oct4, Sox2, and REX1). Both TSH and TSHR-Abs inhibited osteoclastogenesis as evidenced by decreased development of TRAP-positive cells (~40%-50% reduction, p = 0.0047), and by decreased expression, in a concentration-dependent manner, of osteoclast differentiation markers (including the calcitonin receptor, TRAP, cathepsin K, matrix metallo-proteinase-9, and carbonic anhydrase II). Similar data were obtained using serum immunoglobulin-Gs (IgGs) from patients with hyperthyroid Graves' disease and known TSHR-Abs. TSHR stimulators inhibited tumor necrosis factor-alpha mRNA and protein expression, but increased the expression of osteoprotegerin (OPG), an antiosteoclastogenic human soluble receptor activator of nuclear factor кB ligand receptor. Neutralizing antibody to OPG reversed the inhibitory effect of TSH on osteoclast differentiation evidencing that the TSH effect was at least in part mediated by increased OPG.
Conclusion:
These data establish ES-derived osteoclastogenesis as an effective model system to study the regulation of osteoclast differentiation in early development. The results support the observations that TSH has a bone protective action by negatively regulating osteoclastogenesis. Further, our results implicate TSHR-Abs in offering skeletal protection in hyperthyroid Graves' disease, even in the face of high thyroid hormone and low TSH levels.
Insights
Thyroid-stimulating hormone (TSH) and TSH receptor antibodies inhibit osteoclast formation, suggesting a bone-protective role in Graves' disease. This study used embryonic stem cells to model osteoclast development and TSH regulation.
Area of Science:
- Endocrinology
- Bone Biology
- Stem Cell Research
Background:
- Thyroid-stimulating hormone (TSH) inhibits osteoclastic bone resorption.
- TSH receptor (TSHR) null mice exhibit osteoporosis.
- Investigating TSH's role in osteoclast development is crucial for understanding bone remodeling in hyperthyroid Graves' disease.
Purpose of the Study:
- To determine the specific stage of osteoclast development influenced by TSH.
- To examine the effects of TSH and TSHR agonists on osteoclast differentiation from murine embryonic stem (ES) cells.
Main Methods:
- Osteoclast differentiation was induced in murine ES cells using specific growth factors and hormones.
- TSH and TSHR antibodies (TSHR-Ab) were applied to assess their impact on osteoclastogenesis.
- Gene and protein expression of osteoclast markers and regulatory factors were analyzed.
Main Results:
- TSH and TSHR-Abs significantly reduced osteoclast formation (~40%-50%) and expression of key differentiation markers.
- TSHR stimulators increased osteoprotegerin (OPG) expression, an inhibitor of osteoclastogenesis.
- Neutralizing OPG reversed TSH's inhibitory effect, indicating TSH acts partly via OPG.
Conclusions:
- ES cell-derived osteoclastogenesis is a valid model for studying osteoclast regulation.
- TSH exerts a bone-protective effect by negatively regulating osteoclastogenesis.
- TSHR antibodies may offer skeletal protection in hyperthyroid Graves' disease.
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