Commentary & PerspectiveThe MeniscusA Key to Unfolding the Mystery of Osteoarthritis

Commentary on an article by Robert H. Brophy, MD, et al.: Molecular Analysis of Age and Sex-Related Gene Expression in Meniscal Tears with and

without a Concomitant Anterior Cruciate Ligament Tear

Helen Kambic, PhD

Our appreciation of the molecular organization of the meniscus is leading to a greater understanding of its cellular function indisease. Meniscal tears can lead to knee osteoarthritis, but knee osteoarthritis can lead to a spontaneous meniscal tear throughbreakdown of the meniscal structure1. This study is timely and relevant regarding the predicted increase in the prevalence of newcases of osteoarthritis in the young athletic population of both sexes. The cross-reactivity of several molecular markers associatedwith osteoarthritis was demonstrated in the torn meniscus. Although the authors chose an age cutoff of forty years, the age at onsetof meniscal injury influences the primary cellular response. Age-related changes coupled with tear locationwithin the meniscus andcontributions of the synovial fluid could influence gene expression.

There is ample evidence that the meniscus has a related but distinct molecular signature that is different from that found inarticular cartilage. The collagen ultrastructure places the meniscus at risk for longitudinal tears. Torn menisci and concomitantanterior cruciate ligament (ACL) rupture possess unique and specific phenotypic cells and gene expression with combined injuries.One study has noted that genes detected from osteoarthritic meniscal cells differ from normal meniscal cells and are abnormallyexpressed in other types of osteoarthritic cells or tissues, which suggests that differential gene expressions detected may be age-related and/or disease-specific2.

The meniscal status at the time of surgery has been considered an important factor for predicting the development ofosteoarthritis3. Attention is now directed to the identification of biomarkers of key catabolic activities within the torn meniscus. Inthis study, the authors are to be commended for focusing on the gene expression profiles found in the meniscus subject to time-varying changes in mechanical effects due to meniscal tears and for analyzing the correlation between this damage to combinedtears in both the meniscus and ACL. Meniscal tissue was retrieved at the time of partial meniscectomy and divided by sex and age(under and over forty years of age). This approach avoided the changes introduced by cell culture conditions and was validated byquantitative real-time polymerase chain reaction methods and rigorous statistical analyses.

The rationale for the use of the cutoff of forty years of age was based on the fact that torn menisci in mature patients havelower cellularity. More male patients presented with meniscal tears and combined injury in both age groups. These could be theresult of participation in more aggressive sports and manual activities. In other reports, increased age, male sex, and surgical delayincreased the frequency and severity of injuries of the meniscus and/or articular cartilage after an ACL tear4.

The authors point out that the meniscus in younger patients reacts with an intrinsic response and is more prone toinflammatory changes. Intrinsic meniscal degeneration occurs in both men and women and begins at about thirty years of age;degenerative meniscal tears occur in association with age-related degenerative changes in the tissue5. A tear to the meniscus altersthe fibrochondrocytes experiencing the compressive forces at the inner half of the meniscus and subsequently also influences thefibroblast or superficial zone cell metabolism. Evidence for the cross-reactivity of interleukin-1b (IL-1b)-mediated increases in

Disclosure: The author received no payments or services, either di-rectly or indirectly (i.e., via her institution), from a third party in supportof any aspect of thiswork. Neither the author nor her institution has hadany financial relationship, in the thirty-sixmonths prior to submission ofthis work, with any entity in the biomedical arena that could be per-ceived to influence or have the potential to influence what is written inthis work. Also, the author has not had any other relationships, or en-gaged in any other activities, that could be perceived to influence orhave the potential to influence what is written in this work. The com-plete Disclosures of Potential Conflicts of Interest submitted by au-thors are always provided with the online version of the article.

This article was chosen to appear elec-tronically on February 22, 2012, in ad-vance of publication in a regularlyscheduled issue.

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J Bone Joint Surg Am. 2012;94:e31(1-2) d http://dx.doi.org/10.2106/JBJS.K.01593

matrix metalloproteinase (MMP) activity is evident in both the meniscal tear and with combined tears in individuals under the ageof forty years. Aggrecan expression associated with inflammatory cytokines was lower in patients under forty years of age withcombined tears. The response to meniscal injury may be dependent not only on these cells but also on a subpopulation of cellsexpressing a remodeling response to injury5.

What is unique to the study is that in the group of patients over forty years old, there were no differences in inflammatorycytokines or chemokines. An increased expression of the chemokine CCL3L1 was found in meniscal tears in both male and femalepatients; however, this significantly increased in females with combined injury. The combined injury results in more severe damageto the joint than the result of a single meniscal lesion. Remarkably, there were no significant differences among the other genesbased on sex and injury. It would be interesting to know if these markers are consistent over a greater population of patients withprecise identification of the extent of damage to either or both the lateral or medial meniscus. If confirmed in larger studies, thesemarkers may monitor local events at the surgical sites and detect the progression of osteoarthritis. In summary, this article suggeststhat there may be more information hidden in the meniscus than previously thought.

Helen Kambic, PhDStevens Institute of Technology,

Hoboken, New Jersey

References1. Englund M, Guermazi A, Lohmander SL. The role of the meniscus in knee osteoarthritis: a cause or consequence? Radiol Clin North Am. 2009;47:703-12.2. Sun Y, Mauerhan DR, Honeycutt PR, Kneisl JS, Norton JH, Hanley EN Jr, Gruber HE. Analysis of meniscal degeneration and meniscal gene expression. BMC MusculoskeletDisord. 2010;11:19.3. Shelbourne KD, Gray T. Results of anterior cruciate ligament reconstruction based on meniscus and articular cartilage status at the time of surgery. Five- to fifteen-yearevaluations. Am J Sports Med. 2000;28:446-52.4. Slauterbeck JR, Kousa P, Clifton BC, Naud S, Tourville TW, Johnson RJ, Beynnon BD. Geographic mapping of meniscus and cartilage lesions associated with anteriorcruciate ligament injuries. J Bone Joint Surg Am. 2009;91:2094-103.5. Rodeo SA, Kawamura S. Form and function of the meniscus. In: Einhorn TA, OKeefe RJ, Buckwalter JA, editors. Orthopaedic basic science. 3rd ed. Rosemont: AmericanAcademy of Orthopaedic Surgeons; 2007. p 175-89.

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COMMENTARY & PERSPECTIVE