Identifying Anabolic and Catabolic Growth Factor Signals in Osteoarthritis

Objectives: Osteoarthritis (OA) is a debilitating disease caused by deterioration of articular cartilage of the joints. It's well established that articular cartilage responds to injury that causes OA by initiating catabolic responses, which eventually lead to cartilage loss. However, an emerging view is that there’re also anabolic responses occurring shortly after injury in articular cartilage. Catabolic responses in cartilage are mediated in part by Epidermal Growth Factor Receptor (EGFR, also known as ErbB1) signaling. Intriguingly, the EGFR can also mediate anabolic responses in articular cartilage. Most signals transduced by EGFR/ErbB family members are mediated by heterodimers. We hypothesize that the specific catabolic and anabolic activities of the EGFR family are mediated by formation of unique heterodimer pairs. Thus, the goal of this study is to identify potential EGFR/ErbB heterodimers which may mediate distinct catabolic vs. anabolic activities in articular cartilage.
Methods: The activation of EGFR family members in catabolic responses in articular cartilage was examined using knee joints from a surgically induced OA mouse model. For this model, the anterior cruciate ligament was transected to destabilize the joint. Healthy sham-operated joints were used as controls. EGFR family activation in articular cartilage in which anabolic responses are occurring was examined using knee joints from transgenic mice with genetic EGFR gain of function mutation. Wildtype littermates were used as controls. Immunohistochemistry was used to determine the presence of activated EGFR family receptors using antibodies specific for tyrosine kinases phosphorylation.
Results: In OA cartilage, activation of EGFR was observed in the deep zone, where abnormal cellular cloning and hypertrophy occur. Activation of ErbB2 and ErbB4 was observed in the more superficial regions of the articular cartilage, where matrix degradation occurs. In articular cartilage in which anabolic responses are occurring, we observed widespread activation of EGFR and ErbB2 signaling.
Conclusions: Our results support the potential of therapeutic modulation of EGFR/ErbB family signaling targeted to specific dimer pairs at discrete stages of OA progression. This may offer a new interventional approach for OA.