To investigate, Yang and his lab traveled to a deer farm in California where they collected samples of early antler tissue, which is primarily made up of skeletal stem cells. Antlers grow from the top down; so as they grow upward, a reservoir of stem cells remains at the top of the antlers, continuing to proliferate. In early development, antler tissue is soft, much like the cartilage of your nose, making cell sampling an easy task for Yang and harmless for the buck. Only in the second stage of development does the antler mineralize and become rigid.
Back in the lab, the scientists used a variety of techniques to decipher the genetics behind antler growth, including analyses of RNA, a molecule that help carry out specific gene instructions, and gene “knock-down” and “over-expression” studies, which hinder gene function or rev it up, respectively. Comparative RNA analyses between stem cells in deer antlers and human stem cells from bone marrow led Yang to a collection of genes that seemed to have a unique expression in antlers. From that pool, he narrowed the search by tampering with gene function, watching to see how different levels of gene expression affected tissue growth in mouse cells.
In mouse cells, Yang saw that when the uhrf1 gene was decommissioned, the bone tissue could still grow, just not as quickly; only when uhrf1 was fully functional did the scientists see the rapid cell proliferation characteristic of antler growth. Likewise, when s100a10 was overexpressed, calcium deposits increased and the engineered cells more rapidly mineralized.
“Antler regeneration is a unique phenomenon that, to me, is worth studying just out of pure curiosity, but lo and behold, it may have some really interesting applications for human health,” Yang said.
Applying antler genetics to humans
The researchers hope that their insights into antler genes might inform new approaches for treating diseases like osteoporosis. In healthy bones, two types of cells — osteoblasts and osteoclasts — work as opposing forces. Osteoblasts produce new bone tissue, while osteoclasts break down old bone. The two cell types work in a yin and yang style to continuously form and degrade bone to maintain balanced bone structure. In osteoporosis, osteoclast function overtakes osteoblasts, and the bone starts to break down.
“We’re just at the beginning of this research, but our ultimate goal is to figure out how we can apply the same underlying biology that allows for rapid bone regeneration in deer antlers to help treat human bone conditions, such as osteoporosis,” Yang said.
Yang plans to continue researching multiple kinds of deer to confirm that uhrf1 and s100a10 back speedy antler growth across species. In addition, he plans to test how the genes function in human cell lines, while continuing to parse how ufh1 and s100a10 work on a molecular level, looking into possible functional pathways.
“There’s a lot of work to be done, but this could be a unique model of bone regeneration, and our initial work here has started to lay a foundation for future studies,” Yang said.
Other Stanford co-authors of the paper are postdoctoral scholars Dan Wang, PhD, and Bin Zhang, PhD; Norma Neff, PhD, former DNA sequencing core director; former undergraduate researcher Rashmi Sharma; William Maloney, MD,the Boswell Chair of Orthopaedics and professor of orthopedic surgery; and Stephen Quake, PhD, professor of bioengineering and of applied physics and co-president of the Chan Zuckerberg Biohub.
Scientists from the Tenth People’s Hospital of Tongji University, Calico Life Sciences and the State Key Lab for Molecular Biology of Special Economic Animals also contributed to the study.
Stanford’s Department of Orthopedic Surgery also supported the work.