Abstract
Parathyroid hormone (PTH)-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR) play an essential role in controlling growth plate development. The aim of the present study was to use the deer antler as a model to determine whether PTHrP and PPR may also have a function in regulating cartilage and bone regeneration in an adult mammal. Antlers are the only mammalian appendages that are able to undergo repeated cycles of regeneration, and their growth from a blastema involves a modified endochondral process. Immunohistochemistry was used to establish sites of localization of PTHrP and PPR in antlers at different stages of development. The pattern of Indian Hedgehog (IHH) and transforming growth factor-beta1 (TGF beta1) distribution was also investigated, because PTHrP expression in the developing limb is regulated by IHH and during embryonic growth plate formation TGF beta1 acts upstream of PTHrP to regulate the rate of chondrocyte differentiation. In the antler blastema (<10 days of development), PTHrP, PPR, and TGF beta1 were localized in epidermis, dermis, regenerating epithelium, and in mesenchymal cells but IHH expression was not detected. In the rapidly growing antler (weeks 4-8 of development), PTHrP, PPR, and TGF beta1 were localized in skin, perichondrium, undifferentiated mesenchyme, recently differentiated chondrocytes, and in perivascular cells in cartilage but not in fully differentiated hyperytrophic chondrocytes. IHH was restricted to recently differentiated chondrocytes and to perivascular cells in cartilage. In mineralized cartilage and bone, PTHrP, PPR, IHH, and TGF beta1 were immunolocalized in perivascular cells and differentiated osteoblasts. PTHrP and PPR were also present in the periosteum. TGF beta1 in vitro stimulated PTHrP synthesis by cells from blastema, perichondrium, and cartilage. The findings of this study suggest that molecules which regulate embryonic skeletal development and postnatal epiphyseal growth may also control blastema formation, chondrogenesis, and bone formation in the regenerating deer antler. This finding is further evidence that developmental signaling pathways are recapitulated during adult mammalian bone regeneration.
Highlights
An ability to regenerate complex structures is widespread among lower organisms and is retained in some vertebrate species such as anuran amphibians (Goss, 1969; Tanaka et al, 1999)
Numerous factors determine cellular interactions in the embryonic limb, we focused on these molecules, because parathyroid hormone-related peptide (PTHrP) and Indian Hedgehog (IHH) are “master regulators” of chondrocyte proliferation during endochondral bone formation and IHH regulates osteoblast differentiation
Antlers grow by a process of epimorphic regeneration; after the previous set of solid dead antlers are cast off in the spring a blastema forms, which is composed of a healing wound surface and a subjacent layer of mesenchymal cells
Summary
An ability to regenerate complex structures is widespread among lower organisms and is retained in some vertebrate species such as anuran amphibians (Goss, 1969; Tanaka et al, 1999). Adult mammalian examples of epimorphic regeneration are extremely rare with the most dramatic example being the annual replacement of antlers in deer. These large complex bones function as secondary sexual characteristics used for fighting and display in males, in some species, they develop in females (Goss, 1983). Each year the old set of antlers is shed (cast) in the spring and a regeneration blastema forms from which the new set of antlers develops.
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