Deer antlers: a zoological curiosity or the key to understanding organ regeneration in mammals?

Abstract

Many organisms are able to regenerate lost or damaged body parts that are structural and functional replicates of the original. Eventually these become fully integrated into pre-existing tissues. However, with the exception of deer, mammals have lost this ability. Each spring deer shed antlers that were used for fighting and display during the previous mating season. Their loss is triggered by a fall in circulating testosterone levels, a hormonal change that is linked to an increase in day length. A complex 'blastema-like' structure or 'antler-bud' then forms; however, unlike the regenerative process in the newt, most evidence (albeit indirect) suggests that this does not involve reversal of the differentiated state but is stem cell based. The subsequent re-growth of antlers during the spring and summer months is spectacular and represents one of the fastest rates of organogenesis in the animal kingdom. Longitudinal growth involves endochondral ossification in the tip of each antler branch and bone growth around the antler shaft is by intramembranous ossification. As androgen concentrations rise in late summer, longitudinal growth stops, the skin (velvet) covering the antler is lost and antlers are 'polished' in preparation for the mating season. Although the timing of the antler growth cycle is clearly closely linked to circulating testosterone, oestrogen may be a key cellular regulator, as it is in the skeleton of other male mammals. We still know very little about the molecular machinery required for antler regeneration, although there is evidence that developmental signalling pathways with pleiotropic functions are important and that novel 'antler-specific' molecules may not exist. Identifying these pathways and factors, deciphering their interactions and how they are regulated by environmental cues could have an important impact on human health if this knowledge is applied to the engineering of new human tissues and organs.

Fig. 1

The diverse anatomy of antlers. (A) Moose (Alces spp.). >(B) Fallow deer (Dama dama). (C) Red deer (Cervus elapus). B and C are reproduced courtesy of Dr John Fletcher, Reediehill Deer Farm, Auchtermuchty, Fife, UK.

Fig. 2

(A) Schematic diagram to show the three axes of the antler development: A-P, anterior-posterior axis; D-V, dorso-ventral axis; M-L, medio-lateral axis. (B,C) Schematic diagrams illustrating three stages of antler development. (B) Antlerogenic periosteum is present in the embryo and after birth as a localized thickening of the periosteum of the frontal bone. (C) Development of the pedicle occurs through four stages: 1, intramembranous ossification; 2, transitional ossification; 3, pedicle endochondral ossification; 4, antler endochondral ossification and velvet skin formation. (D) Longitudial section through a growing primary antler illustrating the main anatomical regions. Endochondral bone growth occurs at the distal tip while bone forms by intramembranous ossification around the antler shaft.

Fig. 3

Growth of an ‘antler’ from transplanted antlerogenic periosteum. Antlerogenic periosteum was transplanted from the frontal bone and grafted onto the metacarpal bone of a young fallow deer. Photograph courtesy of Uwe and Horst Kierdorf, Justus Liebig University of Giessen, Germany.

Fig. 4

Changes in circulating concentrations of testosterone and the carboxy-terminal pro-peptide of type I collagen (PICP) during the antler growth cycle in red deer stags. Serum samples were collected at post-mortem from deer stags killed for venison at different times of year. PICP was measured by radioimmunoassay (Orion, Diagnostica, Finland) and the values shown are the mean ± SEM. This illustrates that antler regeneration is associated with significant changes in bone turnover. The testosterone graph is adapted from Muir et al. (1988).

Fig. 5

The consequences of the rise in concentrations of circulating testosterone in late summer. (A) Shedding of velvet skin. (B) A pair of boxing stags. (Courtesy of Dr John Fletcher, Reediehill Deer Farm, Auchtermuchty, Fife, UK).

Fig. 6

The effects of castration on antler growth. (A) Antler of an intact red deer stag in early autumn. The velvet skin has been shed following the rise in circulating testosterone levels. (B) Antler of a red deer stag that was orchidectomized during the first month of antler growth; this results in retention of the velvet skin. (C) The antler of a castrated fallow deer. Numerous bony protuberances (‘antleromas’) can be observed over the antler surface. Photograph courtesy of Uwe and Hans Kierdorf, Justus Liebig University of Giessen, Germany.

Fig. 7

Different stages of antler regeneration. (A) The pedicle immediately after the old antler has been cast. Note the ‘ring’ of regenerating tissue around the edge (arrowheads). (Courtesy of Dr John Fletcher, Reediehill Deer Farm, Auchtermuchty, Fife, UK). (B) The early antler bud ∼4 days after antler casting. A scab has now formed. Asterisk indicates the position of a future branch. (C) Antlers at ∼30 days of growth showing the anterior (brow) and posterior (main beam) tines (arrows). (D–F) Schematic diagrams of sections through the regenerating antler. PP, periosteum of pedicle; PS, pedicle skin; GT, ‘granulation’ tissue; PC, perichondrium; UM, undifferentiated mesenchymal tissue; PC, perichondrium; CP, chondroprogenitors; CART, cartilage; PA, periosteum of the antler. (D) Day zero. Casting leaves an exposed pedicle bone surface upon which a scab forms (as in B). (E) Antler bud at about days 9–10. The migrating wound epithelium has almost completely covered the pedicle surface. The underlying tissue has features of granulation tissue but also contains undifferentiated mesenchymal cells, so we describe this as ‘undifferentiated mesenchyme’. Growth centres have been established at the sites where branches will develop and chondrogeneis is evident beneath them (marked by an asterix). (F) Day 30. Longitudinal growth takes place in the distal tip of each branch. D is adapted from Li et al. (2005).

Fig. 8

Histology of the early regenerating antler. Haematoxylin and eosin (H&E)-stained undecalcified paraffin sections. (A) The migratory wound epithelium (W) overlying undifferentiated mesenchyme (UM) and granulation tissue (GT) in the centre of the antler bud at day 4. S, scab. Inset: a higher magnification view of mesenchymal tissue. (B) By day 9 there is a distinct zone of chondroprogenitors (CPs) and longitudinally aligned vascular channels (v). (C) Cartilage formation in the 9-day antler. Chondrocytes (CH) are surrounded by cartilage matrix and pervascular mesencymal tissue (PV). (D) Recent bone (B) formation. Osteoblasts are marked with arrowheads.

Fig. 9

Histology of the regenerating antler during rapid longitudinal growth. (A) Longitudinal tissue section of antler tip to show macroscopic appearance of regions: v, velvet skin; p, perichondrium; m, mesenchyme; cp, chondroprogenitor region; c, cartilage; bo, bone; po, periosteum. Scale bar = 0.5 cm. (B–J) H&E-stained undecalcified paraffin sections of the tissue regions shown in A. (B) Velvet skin. e, epidermis; d, dermis; h, hair follicle; s, sebaceous gland. (C) Fibrous perichondrium. A blood vessel is marked by an arrowhead. (D) Mesenchymal ‘growth zone’. (E) Chondroprogenitor (cp) region. As in the early antler bud, cells start to become aligned in ‘columns.’ However, the vascular spaces are relatively small (arrowhead). (F) Non-mineralized cartilage. Recently differentiated chondrocytes (ch) are arranged in trabeculae separated by larger vascular channels (v). (G) Mineralized cartilage region. Chondrocytes and the vascular channels (v) increase in size in this region. (H) Spongy bone in the mid shaft of the antler that has formed by endochondral ossification. Osteoblasts are marked with an arrowhead. (I) Fibrous (f) and cellular (c) layers of the antler periosteum. (J) Intramembranous bone formation (b) takes place beneath the cellular periosteum (c). Scale bar (B–J), 100 µm.