Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University Frankfurt/Main, 60528, Germany.
Department of Orthopedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology, University of Regensburg Regensburg, 93053, Germany.
Osteoarthritis Cartilage. 2022 Mar;30(3):461-474. doi: 10.1016/j.joca.2021.11.016. Epub 2021 Dec 2.
Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model.
Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and β2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings.
Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice.
Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.
骨关节炎（OA）的发病机制涉及关节软骨与周围组织的相互作用，这些组织被酪氨酸羟化酶阳性（TH+）交感神经纤维支配，这表明交感神经系统（SNS）在 OA 进展过程中起作用。我们分析了交感神经切除术（Syx）在小鼠 OA 模型中的作用。
通过 6-羟多巴胺（6-OHDA）注射在雄性 C57BL/6 小鼠中产生外周 Syx。通过内侧半月板不稳定（DMM）在野生型（WT）和 Syx 小鼠中诱导 OA。分析 TH+纤维和脾去甲肾上腺素（NE）以评估 Syx 效率。通过 OARSI 和滑膜炎评分以及 micro-CT 检查 OA 进展。通过染色研究 TH、α2A-和β2-肾上腺素能受体（AR）的表达以及成骨细胞（ALP）和破骨细胞（TRAP）的活性。
Syx 导致滑膜 TH+纤维消除和脾 NE 减少。DMM 后软骨降解和滑膜炎在 WT 和 Syx 小鼠中均呈进行性进展。与 WT 相比，8 周后 DMMWT 和 Syx 小鼠的钙化软骨（CC）和软骨下骨板（SCBP）厚度和骨体积分数（BV/TV）增加，因为 ALP 增加和 TRAP 活性降低导致 Syx 小鼠的 CC 和 SCBP 厚度和骨体积分数（BV/TV）增加。与 WT 相比，WT 和 Syx 小鼠的软骨中 AR 数量减少，而滑膜和骨赘区域增加。
外周 SNS 活性减弱加重了 OA 特异性软骨钙化和软骨下骨增厚，但不影响软骨降解和滑膜炎。因此，SNS 可能是开发治疗软骨下骨病变新治疗策略的有吸引力的靶点。
