Maturating Articular Cartilage Can Induce Ectopic Joint-Like Structures in Neonatal Mice

Osteoarthritis is a huge health burden to our society. Seeking for potential ways to induce regeneration of articular cartilage (AC) that is intrinsically limited, we focused on the interaction between two opposing joints. To evaluate the role of the interaction of opposing regions of AC for joint maturation, we amputated digits at the distal interphalangeal level without injuring the articular surface of the intermediate phalanx (P2) and observed that the zonal organization of AC was defective. We then removed the P2 bone without injuring the articular surface of the proximal phalanx (P1), and the remaining part of the digit was amputated near the distal interphalangeal level. The distribution pattern of type II collagen and proteoglycan 4 (PRG4) suggested that maturation of AC in P1 was delayed. These two experiments suggested that an interaction between the opposing AC in a joint is necessary for maturation of the zonal organization of AC in neonatal digits. To test if an interaction of the joints is sufficient to induce articular cartilage, a proximal fragment of P2 was resected, inverted, and put back into the original location. Newly formed cartilage was induced at the interface region between the AC of the inverted graft and the cut edge of the distal part of P2. Type II collagen and PRG4 were expressed in the ectopic cartilage in a similar manner to normal AC, indicating that neonatal AC can induce ectopic joint-like structures in mice comparable with what has been reported in newts and frogs. These results suggest that the neonatal joint could be a source of inductive signals for regeneration of AC. In this study, we experimentally show that neonatal mice appear to have the capacity to regenerate articular cartilage (AC) in digits. It is already known that mice can regenerate a digit tip after amputation, but do not regenerate in response to amputations at more proximal levels. Therefore, it has been thought that mammalian joint structures are non-regenerative. However, we found that normal digit AC can induce AC-like structures in a non-joint region when it is placed next to the cut edge of a bone, suggesting that the normal AC has regenerative capacity in certain situations in neonatal mice. Joint disorders are a huge health problem of our society. The results of this study suggest that neonatal AC could be a potential source of inductive signals for regeneration of AC. The discovery of these inductive signals will aid in developing regenerative therapies of a joint in human.