Open Access Open Badges Research article

Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis

Akihiko Hasegawa12, Hiroyuki Nakahara1, Mitsuo Kinoshita2, Hiroshi Asahara1, James Koziol1 and Martin K Lotz1*

Author affiliations

1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

2 Department of Orthopedic Surgery, Osaka Medical College, 2-7 Daigakumachi Takatsuki, Osaka 569-8686, Japan

For all author emails, please log on.

Citation and License

Arthritis Research & Therapy 2013, 15:R29  doi:10.1186/ar4165

Published: 14 February 2013



Anterior cruciate ligament (ACL) degeneration is observed in most osteoarthritis (OA)-affected knee joints. However, the specific spatial and temporal relations of these changes and their association with extracellular matrix (ECM) degeneration are not well understood. The objective of this study was to characterize the patterns and relations of aging-related and OA-associated changes in ACL cells and the ECM.


Human knee joints from 80 donors (age 23 through 94) were obtained at autopsy. ACL degeneration was assessed histologically by using a quantitative scoring system. Tissue sections were analyzed for cell density, cell organization, ECM components, ECM-degrading enzymes and markers of differentiation, proliferation, and stem cells.


Total cell number in normal ACL decreased with aging but increased in degenerated ACL, because of the formation of perivascular cell aggregates and islands of chondrocyte-like cells. Matrix metalloproteinase (MMP)-1, -3, and -13 expression was reduced in aging ACL but increased in degenerated ACL, mainly in the chondrocyte-like cells. Collagen I was expressed throughout normal and degenerated ACL. Collagen II and X were detected only in the areas with chondroid metaplasia, which also expressed collagen III. Sox9, Runt-related transcription factor 2 (Runx2), and scleraxis expression was increased in the chondrocyte-like cells in degenerated ACL. Alpha-smooth muscle actin (α-SMA), a marker of myofibroblasts and the progenitor cell marker STRO-1, decreased with aging in normal ACL. In degenerated ACL, the new cell aggregates were positive for α-SMA and STRO-1.


ACL aging is characterized by reduced cell density and activation. In contrast, ACL degeneration is associated with cell recruitment or proliferation, including progenitor cells or myofibroblasts. Abnormally differentiated chondrocyte-like cell aggregates in degenerated ACL produce abnormal ECM and may predispose to mechanical failure.