Abstract
PurposeRecent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/- ) mice after surgical OA induction.MethodsOA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.ResultsWT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.ConclusionWe propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.
Highlights
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease that affected worldwide 303 million people in 2017 [1]
Various b2-adrenergic receptors (ARs)-mediated effects of the sympathetic nervous system (SNS) on chondrocytes, synoviocytes or cells of the subchondral bone regarding OA pathogenesis have been described by recent studies [9]
We demonstrated that b2-AR deficiency had no influence on articular cartilage degradation and OA-related synovitis, the thickness of calcified cartilage and OA-related subchondral bone changes were aggravated compared to the respective WT control animals
Summary
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease that affected worldwide 303 million people in 2017 [1]. OA pathogenesis involves the whole joint with destruction of cartilage, inflammation of synovium, formation of osteophytes, sclerosis of subchondral bone as well as degeneration of ligaments and menisci. These pathological processes lead to the major symptoms joint stiffness and pain, which result in limited movement and reduced quality of life and in immense socio-economic costs. There is still no causal therapy that effectively addresses joint degeneration and inflammation, only symptomatic treatments exist aiming to reduce pain [5]. Joint replacement is often the last effective therapy [6]. In order to develop novel therapeutic options, it is essential to better understand the multifactorial pathophysiology of OA
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