Abstract
Objective
Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.
Methods
Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with congenital Bscl2 KO mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically.
Results
The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα+ Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice with intra-articular lipodystrophy showed increased susceptibility to the cartilage damaging effects of HFD-induced obesity.
Conclusion
Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.
Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.
Methods
Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with congenital Bscl2 KO mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically.
Results
The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα+ Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice with intra-articular lipodystrophy showed increased susceptibility to the cartilage damaging effects of HFD-induced obesity.
Conclusion
Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.
| Original language | English |
|---|---|
| Journal | Osteoarthritis and Cartilage |
| Early online date | 3 Aug 2024 |
| DOIs | |
| Publication status | E-pub ahead of print - 3 Aug 2024 |
Bibliographical note
The authors thank all members and research project students of the Arthritis and Regenerative Medicine Laboratory at the University of Aberdeen. The authors are also grateful to Animal Facility staff for care of our animals, and staff in the Microscopy and Histology Facility and the qPCR Facility for their expert support. Part of this work has been previously presented at OARSI 2022 World Congress: J.J. McClure, G.D. McIlroy., F. Colella, R.A. Symons, S.M. Clark, J.J. Rochford, C. De Bari, A.J. Roelofs. Decreased intra-articular adipose tissue in the knee joint does not affect osteoarthritis development in mice. Osteoarthr Cartil 2022;30:S334.Data Availability Statement
All data supporting the findings of this study are available within the Article and its Supplementary Information files, or are available from the corresponding author upon reasonable request.Keywords
- Osteoarthritis
- obesity
- infrapatellar fat pad
- articular cartilage
- lipodystrophy
