The influence of macrophage depletion on ligament healing.
Despite a complex cascade of cellular events to reconstruct damaged extracellular matrix (ECM), ligament healing results in a mechanically inferior, scar-like tissue. During normal healing, the number of macrophages significantly increases within the wound site. Then, granulation tissue expands into any residual, normal ligamentous tissue (creeping substitution), resulting in a larger region of healing, greater mechanical compromise, and an inefficient repair process. To study the effects of macrophages on the repair process, bilateral, surgical rupture of their medial collateral ligaments (MCLs) was done on rats. Treatment animals received liposome-encapsulated clodronate, 2 days before rupture to ablate phagocytosing macrophages. Ligaments were then collected at days 5, 11, and 28 for immunohistochemistry (IHC) and/or mechanical testing. Clodronate treatment reduced both the M1 and M2 macrophages at day 5 and altered early healing. However, the macrophages effectively returned to control levels after day 5 and reinitiated a wound-healing response. Our results suggest that an early macrophage response, which is necessary for debridement of damaged tissue in the wound, is also important for cytokine release to mediate normal repair processes. Additionally, nonspecific inhibition of macrophages (without regard to specific macrophage populations) can control excessive granulation tissue formation but is detrimental to early matrix formation and ligament strength.
Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, USA.
Connie S
CS
Chamberlain
Ellen M
EM
Leiferman
Kayt E
KE
Frisch
Sijian
S
Wang
Xipei
X
Yang
Nico
N
van Rooijen
Geoff S
GS
Baer
Stacey L
SL
Brickson
Ray
R
Vanderby
D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008081:Liposomes / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D017888:Medial Collateral Ligament, Knee / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
D008081:Liposomes; D004002:Clodronic Acid; D003094:Collagen