Estrogen Deficiency Exacerbates Traumatic Heterotopic Ossification in Mice

Area of Science:

• Orthopedics
• Endocrinology
• Immunology

Background:

• Traumatic heterotopic ossification (HO) is a common complication following orthopedic surgery and injuries.
• The role of estrogen deficiency in HO development remains under-investigated.
• This study examines the impact of estrogen deficiency on HO formation in a mouse Achilles tenotomy model.

Purpose of the Study:

• To investigate the effect of estrogen deficiency on ectopic cartilage and bone formation after Achilles tenotomy.
• To elucidate the underlying mechanisms, including inflammatory responses and TGF-β/SMAD signaling.

Main Methods:

• Ovariectomized (OVX) mice, OVX mice with 17β-estradiol (E2) supplementation, and sham-operated controls were used.
• Achilles tenotomy was performed to induce HO.
• Histology, immunohistochemistry, immunofluorescence, and micro-CT were employed to assess HO formation, inflammation, and signaling pathways at various time points.

Main Results:

• Estrogen deficiency significantly increased ectopic cartilage and bone formation compared to controls.
• OVX mice exhibited heightened inflammatory infiltration and elevated pro-inflammatory mediators (IL-1β, IL-6, TNF-α).
• Dysregulated TGF-β/SMAD signaling, with upregulated TGF-β and pSMAD2/3, was observed in OVX mice; E2 supplementation reversed these changes.

Conclusions:

• Estrogen deficiency exacerbates HO formation in the Achilles tenotomy model.
• This exacerbation is linked to disturbed inflammatory responses and activated TGF-β/SMAD signaling.
• Estrogen plays a protective role against HO development, potentially through modulation of inflammation and TGF-β/SMAD signaling.