Nearly 19% of american women aged 50 and older have osteoporosis in their hips and lower spines. Osteoporosis-associated weakening of the bones increases the risk of fractures and poses significant risks to health and quality of life. Several medications are approved to treat osteoporosis but fears of rare, severe side effects often are a barrier for their use. Treatments that leverage the hormone estrogen also are available, but are only recommended for low-dose, short-term use due in part to associations with cancer risk. It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Sex chromosomes are the fundamental genetic difference between sexes. Discovering how X- or Y-linked genes contribute to sex-dependent bone mass regulation has the potential to lead to the development of promising therapeutics for osteoporosis in women.
An increasing number of studies have revealed that osteoclast differentiation and activity are controlled by epigenetic regulation, largely through controlling the transcriptional machinery on key genes. However, until now, the epigenetic factors that regulate osteoclast differentiation and function have been found to work similarly in both sexes. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age. Van Andel Institute scientists have pinpointed a key driver of low bone density, a discovery that may lead to improved treatments with fewer side effects for women with osteoporosis. They focused on specialized cells called osteoclasts, which help maintain bone health by breaking down and recycling old bone. The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down the recycling process and preserved bone mass.
Importantly, KDM5C is linked to X chromosomes which means it is more active in females than in males. KDM5C (also called JARID1C and SMCX) is an X-linked lysine histone H3 demethylase that escapes X inactivation, resulting in higher expression in females than males. Males express a paralog from chromosome Y, KDM5D, which is also a histone H3 demethylase. The research reveals that loss of KDM5C, preserves bone mass in mice. KDM5C works by altering epigenetic “marks,” which are akin to “on” and “off” switches that ensure the instructions written in DNA are used at the right time and in the right place. To figure out why this happens, the joint scientist teams looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. The findings of the investigation are reported in a paper published this month in Science Advances
Dr Krawczyk, leader of the project, concluded: “Lowering KDM5C levels is like flipping a switch to stop an overactive recycling process. The result is more bone mass, which ultimately means stronger bones. We’re very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Liu HÂ et al. Sci Advances 2023 Apr; 9(14):eadg0731.
Liu H et al. bioRxiv. 2023 Feb 23:2023.02.23.529728.
Schonfeld M et al. Hepatol Commun. 2022; 6(8):2042.