Chondrogenesis And Bmp2-induced Regeneration Of The Adult Mouse Middle Phalanx (p2) Post Amputation
Humans and mice lack the broad regenerative capacity of Urodele amphibians, capable only of partial regeneration of the terminal phalanx (P3), i.e., amputation mid-way through P3 results in essentially complete regeneration of the digit tip mediated via blastema formation and subsequent direct bone formation, culminating in distal bone growth, patterning, and function. Conversely, amputation injuries occurring proximal to the mid-point of P3 result in scar formation. Here, in part, we studied the endochondral bone healing response following amputation of the middle phalanx (P2). We showed the endochondral ossification healing response post amputation of P2 is analogous to the fracture healing response of P2 and other long bones of the body, ultimately proving useful in yielding insight into effectively inducing regeneration of the amputated digit. We showed the periosteal-derived chondrocytes of P2 play an integral role in the bone healing process in that they provide a template for subsequent bone formation following amputation injury. We also showed the periosteal-derived cells can be targeted through the temporal application of BMP2 to accumulate and proliferate at the distal digit tip and thus induce regeneration of the amputated bone. Our studies indicated that P2 amputation injuries of various time points, i.e. previously healed injuries, can be induced to regenerate via re-wounding of the periosteal tissue and subsequent BMP2 application, and thus is immeasurably promising from a translational therapeutic perspective. Lastly, we studied the fracture healing response in conjunction with the intramembranous regeneration response of P3. Following fracture of the digit, we showed the relative lack of periosteal callus formation, the lack of periosteal chondrogenesis, and a novel endosteal/marrow chondrogenic response. Unlike P2, the periosteal tissue of the fractured P3 bone does not respond to BMP2-treatment via endochondral bone growth, instead the bone heals via intramembranous ossification, possibly via intrinsic differentiation limitations and extrinsic factors. Notably, we showed that in the absence of the periosteal tissue of the amputated P3 bone, the regeneration response was greatly attenuated. Taken together, our work blending regeneration and fracture repair may prove useful in enhancing regeneration studies with methods and ideas not previously considered.