Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

Abstract

Skeletal regenerative medicine aims to repair or regenerate skeletal tissues using pharmacotherapies, cell-based treatments, and/or surgical interventions. The field is guided by biological principles active during development, wound healing, aging, and carcinogenesis. Skeletal development and tissue maintenance in adults represent highly intricate biological processes that require continuous adjustments in the expression of cell type-specific genes that generate, remodel, and repair the skeletal extracellular matrix. Errors in these processes can facilitate musculoskeletal disease including cancers or injury. The fundamental molecular mechanisms by which cell type-specific patterns in gene expression are established and retained during successive mitotic divisions require epigenetic control, which we review here. We focus on epigenetic regulatory proteins that control the mammalian epigenome at the level of chromatin with emphasis on proteins that are amenable to drug intervention to mitigate skeletal tissue degeneration (e.g., osteoarthritis and osteoporosis). We highlight recent findings on a number of druggable epigenetic regulators, including DNA methyltransferases (e.g., DNMT1, DNMT3A, and DNMT3B) and hydroxylases (e.g., TET1, TET2, and TET3), histone methyltransferases (e.g., EZH1, EZH2, and DOT1L) as well as histone deacetylases (e.g., HDAC3, HDAC4, and HDAC7) and histone acetyl readers (e.g., BRD4) in relation to the development of bone or cartilage regenerative drug therapies. We also review how histone mutations lead to epigenomic catastrophe and cause musculoskeletal tumors. The combined body of molecular and genetic studies focusing on epigenetic regulators indicates that these proteins are critical for normal skeletogenesis and viable candidate drug targets for short-term local pharmacological strategies to mitigate musculoskeletal tissue degeneration.

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

“…( Madan and Grime, 2015 ). Several epigenetics manners have been investigated in this field ( Tu et al, 2019 ; van Wijnen and Westendorf, 2019 ). Among them, the alteration of m 6 A modification has been associated with the initiation and progression of musculoskeletal diseases.…”

The epigenetic reader Brd4 is required for osteoblast differentiation

“…Histone tail modifications are dynamic and can be altered by epigenetic regulators, proteins that read, write, and erase these marks. The resulting epigenomic landscape is complex and has been show to modulate osteogenic gene expression and bone formation (Dudakovic & van Wijnen, ; Gordon, Stein, Westendorf, & van Wijnen, ; Mortada & Mortada, ; van Wijnen & Westendorf, ).…”

Association of NLRP3 and CARD8 Inflammasome Polymorphisms With Aseptic Loosening After Primary Total Hip Arthroplasty

“…On the other hand, it could also represent the mechanisms by which the inflammatory loop is triggered into a long‐term inflammatory phenotype . In this regard, our results emphasize that analyses of isolated single gene polymorphisms may not produce any significant findings; only by taking into account combinations of several genes or entire gene expression pathways may we be able to pinpoint the risk factors and propose the basis for modulation or treatment of such pathways …”

“…While problems with abrasive wear of implanted hip arthroplasty materials and treatment of infections have been adequately addressed, the etiology of the non‐mechanical non‐infectious aseptic loosening of hip endoprostheses has not been established yet . The time period from implantation to aseptic loosening varies significantly between different patients with identical implants, and recent studies in this field have focused attention to possible differences in genetic host factors and polymorphisms with variability in the immune response to exogenous materials and a different response of individuals’ host tissues to external mechanical stimuli …”