Jason Noor

Background: Avascular necrosis of the femoral head is an orthopedic disease that occurs when the femoral head receives an inadequate supply of blood. This eventually leads to deterioration or collapse of the femoral head.¹ The most common non-traumatic risk factor of avascular necrosis of the femoral head is prolonged use of glucocorticoids.¹ Avascular necrosis is commonly treated with hip arthroplasty, however revision and general post operative complication rates increase in patients younger than 50 years old.^2,3 This issue necessitates the use of alternative treatments, particularly, mesenchymal stem cell therapy.⁴ Bone marrow mesenchymal stem cells (BMSC) can be expanded in culture from a few mLs of BM. They can then be induced to differentiate into the osteoblasts needed to stop or reverse the progression of SANFH. MicroRNAs (miR) are mRNA regulators that inhibit translation of gene expression including those that drive SANFH pathology. Inhibiting microRNAs, like miR-141 and miR-145, have been hypothesized to promote the differentiation of BMSC into osteoblasts within the context of SANFH.

Objective: This narrative review aims to explore the mechanisms of miR-141 and miR-145 inhibition, and evaluate their potential as therapeutic targets in SANFH patients under the age of 50.

Search Methods: An online search on the PubMed database was conducted with parameters limiting the search from 2018 to 2024. The keywords used were: “Bone marrow mesenchymal stem cells,” “steroid induced avascular necrosis,” “microRNA,” and “hip arthroplasty.”

Results: MiR-141 was identified as a regulator of bone mesenchymal stem cell proliferation by initial expression studies employing quantitative reverse transcriptase PCR. Bone mesenchymal stem cells taken from patients with steroid induced avascular necrosis of the femoral head displayed upregulation of miR-141.⁵ SRY-related HMG box 11 (SOX 11) was associated with proliferation of the BMSCs through PCR-based assays. miR-141 was directly associated with a reduction in SOX11 in rat femoral head bone marrow by comparison of a steroid-treated and control group with SOX-11. Further experiments demonstrated that miR-141 inhibition attenuated the reduction in SOX11 expression^4,5 Gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) codes for a protein that is involved in autophagy. GABARAPL1 dysregulation can negatively affect bone turnover. It was established that miRNA-145 was an upstream regulator of GABARAPL1 in a population of 21 patients with SANFH when compared to 21 control patients. Dual luciferase assay was used to confirm that the upregulation of miR-145 had an inverse downstream effect on GABARAPL1. Inhibition of miR-145 may upregulate GABARAPL1 and potentially promote proliferation and apoptosis in bone mesenchymal stem cells of the femoral head.^4,6

Conclusion: SOX11 is upregulated by inhibiting miRNA-141, but its role in osteogenesis is unclear. It is best used as a marker of BMSC proliferation in the context of the presented study.⁵ Inhibiting miRNA-145 upstream of GABARAPL1 promotes osteogenesis because of GABARAPL1’s role in stabilizing bone turnover.⁶ These findings suggest miRNA-141 and miRNA-145 could serve as potential therapeutic targets for young patients with SANFH. However, like all preclinical therapeutics, development of these treatments face challenges based on physician reimbursement considerations for total hip arthroplasty, but these concerns may be offset by the benefits of accelerated functional recovery offered to the patient.

Works Cited:

1. Huang C, Qing L, Xiao Y, Tang J, Wu P. Insight into Steroid-Induced ONFH: The Molecular Mechanism and Function of Epigenetic Modification in Mesenchymal Stem Cells. Biomolecules. 2023;14(1):4. Published 2023 Dec 20. doi:10.3390/biom14010004
2. Kahlenberg CA, Swarup I, Krell EC, Heinz N, Figgie MP. Causes of Revision in Young Patients Undergoing Total Hip Arthroplasty. J Arthroplasty. 2019;34(7):1435-1440. doi:10.1016/j.arth.2019.03.014
3. Nugent M, Young SW, Frampton CM, Hooper GJ. The lifetime risk of revision following total hip arthroplasty. Bone Joint J. 2021;103-B(3):479-485. doi:10.1302/0301-620X.103B3.BJJ-2020-0562.R2
4. Wang X, Hu L, Wei B, Wang J, Hou D, Deng X. Regenerative therapies for femoral head necrosis in the past two decades: a systematic review and network meta-analysis. Stem Cell Res Ther. 2024;15(1):21. Published 2024 Jan 25. doi:10.1186/s13287-024-03635-1
5. Meng CY, Xue F, Zhao ZQ, Hao T, Guo SB, Feng W. Influence of MicroRNA-141 on Inhibition of the Proliferation of Bone Marrow Mesenchymal Stem Cells in Steroid-Induced Osteonecrosis via SOX11. Orthop Surg. 2020;12(1):277-285. doi:10.1111/os.12603
6. Xu P, Chang J, Ma G, et al. MiR-145 inhibits the differentiation and proliferation of bone marrow stromal mesenchymal stem cells by GABARAPL1 in steroid-induced femoral head necrosis. BMC Musculoskelet Disord. 2022;23(1):1020. Published 2022 Nov 26. doi:10.1186/s12891-022-05928-z