Researchers here explore a role for HDAC9 in the progression of osteoporosis, the progressive loss of bone density with age. The signs suggest that age-related upregulation of HDAC9 is involved in cellular senescence and the disruption of cell populations responsible for creating bone tissue. Bone tissue is constantly remodeled, created by osteoblast cells and destroyed by osteoclast cells. The proximate cause of osteoporosis is that the activity of osteoclasts comes to outweigh that of osteoblasts, removing bone structure faster than it is deposited. Many mechanisms that might contribute to this imbalance have been investigated over the years, but it remains unclear as to how exactly they all fit together, and which are the most important.

Osteoporosis is a common aged-related disease and is characterized by decrease bone mass and bone mineral density, leading to bone fragility and a higher risk of fractures. Researchers have discovered several risk factors associated with osteoporosis, including genetic and epigenetic factors, hormone imbalance, and stem cell senescence. Bone marrow mesenchymal stem cells (BMMSCs) are a group of cell residual in the bone marrow. They have self-renewal capacity and multilineage differentiation potential. There is considerable data showing that BMMSCs play crucial roles in maintaining bone remodeling, reparation, and regeneration. Importantly, the number of BMMSCs declines and their lineage commitment shifts from osteoblasts to adipocytes with aging leading to an imbalance between bone mass and bone marrow fat. This imbalance is considered to be a hallmark of aged-related bone loss disorder, osteoporosis.

During senescence, mesenchymal stem cells (MSCs) undergo epigenetic and transcriptional changes, including decreased expression of stemness genes, Oct4 and Nanog, and increased age-related genes, p16 and p53. Some adverse factors that trigger MSC senescence have been identified, such as reactive oxygen species (ROS) accumulation, telomere shortening, and epigenetic effectors, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). However, the details of the epigenetic regulation network remain elusive and its roles in BMMSCs during aged-related bone loss remain to be established.

HDACs are important epigenetic regulators that control gene transcription by removing acetyl groups. In this study, we report that HDAC9 plays an important role in maintaining the balance between osteogenesis and adipogenesis of BMMSCs during aged-related bone mass loss. Furthermore, we found that the downregulation of HDAC9 could partially reverse the differentiation of aging BMMSCs and bone loss in mice by regulating autophagy. These results suggest that aged-related bone mass loss may be partially controlled by the HDAC9-meditated autophagy of BMMSCs.