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Early Unloading After ACL Rupture and Prior to Surgical Restabilization in Mice Slows Post-Traumatic Osteoarthritis

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Early joint unloading after anterior cruciate ligament (ACL) injury slows post-traumatic osteoarthritis (PTOA) progression in mice by modulating the inflammatory response. However, subsequent surgery may exacerbate bone loss.

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Area of Science:

  • Orthopedics
  • Immunology
  • Regenerative Medicine

Background:

  • Anterior cruciate ligament (ACL) rupture often leads to post-traumatic osteoarthritis (PTOA).
  • A delay exists between ACL injury and surgical reconstruction, during which joint loading is unclear.
  • The impact of early joint unloading on PTOA development is not well understood.

Purpose of the Study:

  • To investigate the effect of early hindlimb unloading (HLU) on PTOA progression in a mouse model.
  • To determine how joint unloading between non-invasive ACL injury and surgical restabilization influences PTOA.

Main Methods:

  • Mice underwent non-invasive ACL injury or sham procedure.
  • One week of HLU or normal cage activity followed.
  • Mice then underwent restabilization surgery or no surgery.
  • Epiphyseal trabecular bone, chondrophyte/osteophyte formation, OA score, synovitis, and immune cell populations were assessed.

Main Results:

  • ACL injury caused significant epiphyseal trabecular bone loss.
  • HLU significantly reduced chondrophyte/osteophyte formation, OA scores, and synovitis.
  • Single-cell RNA sequencing showed HLU increased neutrophils and decreased monocytes-macrophages in the joint.
  • Restabilization surgery increased inflammatory protease activity and exacerbated bone loss without significantly impacting OA score or synovitis.

Conclusions:

  • Early HLU (1 week) effectively slowed PTOA progression post-ACL injury.
  • Joint instability and early inflammation are key drivers of PTOA.
  • Neutrophils and monocytes-macrophages play a role in PTOA modulation.
  • Subsequent restabilization surgery may have detrimental effects on bone health despite not worsening OA scores.