β2-adrenoceptor deficiency in experimental osteoarthritis leads to exacerbation of subchondral bone changes without affecting cartilage and synovium

Introduction

Recent studies demonstrated a contribution of the sympathetic nervous system and its major neurotransmitter norepinephrine (NE) to osteoarthritis (OA) pathogenesis. The effects of NE are predominantly catabolic in cartilage and subchondral bone, while mainly anti-inflammatory in the synovial tissue [1] [2]. Several adrenoceptor (AR) subtypes are expressed in different joint tissues [3] but the current literature suggests that the β2-AR plays a crucial role during OA pathogenesis [4] [5] [6]. Therefore, we examined the progression of surgically induced OA in β2-AR-deficient (Adrb2^-/-) mice.

Material and Methods

OA was induced by destabilization of the medial meniscus (DMM) in wild type (WT) and Adrb2^-/- mice. 8 weeks after DMM or sham surgery, body weight was determined. Bone parameters such as subchondral bone plate (SCBP) thickness, bone volume over total volume (BV/TV), trabecular thickness (Tb.Th), trabecular space (Tb.Sp) were analyzed by micro-computed tomography (µCT), and the severity of OA was assessed by histological scoring (OARSI and synovitis grade).

Results

Adrb2^-/- mice had significantly higher body weight compared to WT mice (Adrb2^-/- 33.94±0.87 g, WT 28.67±0.18 g; p=<0.0001). In sham animals, there were no significant differences in bone parameters between WT and Adrb2^-/-. In contrast, DMM-operated Adrb2^-/- mice displayed significantly increased subchondral bone plate thickness (WT DMM 107.7±3.1 μm, Adrb2^-/- DMM 160.01±14.27 μm; p=0.0098), BV/TV (WT DMM 0.563±0.029, Adrb2^-/- DMM 0.697±0.026; p=0.014) and Tb.Th (WT DMM 0.08±0.008 mm, Adrb2^-/- DMM 0.506±0.084 mm; p=0.0055) in the medial epiphysis. At the same time, Tb.Sp was significantly decreased (WT DMM 0.054±0.002 mm, Adrb2^-/- 0.022±0.005 mm; p<0.0001). WT and Adrb2^-/- mice subjected to DMM developed comparable changes in cartilage degeneration and synovial inflammation (mean OARSI score: WT DMM 3.00±0.47, Adrb2^-/- DMM 2.85±0.57; mean synovitis score WT DMM 2.86±0.26, Adrb2^-/- 2.75±0.25).

Conclusion

Subchondral sclerosis is a hallmark of OA. We observed an increased bone mass in Adrb2^-/- DMM versus WT DMM mice. This is consistent with earlier studies reporting an anti-osteogenic effect of β2-AR. However, we did not detect any difference between bone parameters of sham-operated WT and Adrb2^-/- animals suggesting that increased bone mass in Adrb2^-/- DMM mice is attributed to a synergistic effect of β2-AR deficiency and OA. The elevated body weight in Adrb2^-/- mice might result in increased mechanical joint loading. However, this was not sufficient to induce a more pronounced cartilage degeneration and synovitis than in WT mice. Taken together, β2-AR plays an important role in OA-related bone changes and could thus be an attractive target for novel therapeutic treatments.

Conflict of Interest

The authors declare that there are no conflicts of interest.

• References

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• 4 Aitken et al. Arch Biochem Biophys 2009, vol. 482, no. 1–2, pp. 96–103
• 5 Pai et al. J Cell Biochem 2008, vol. 104, no. 2, pp. 545–53
• 6 Miller et al. J Rheumatol 2002, vol. 29, no. 3, pp. 427–35

Publication History

Article published online:
04 November 2021