Translational research : the journal of laboratory and clinical medicine · 2026
Pharmacological neutralization of the Rspo2/Wnt axis preserves subchondral bone plate and vascular niche integrity to attenuate cartilage degeneration in osteoarthritis.
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Guo Dong, Yang Lingfeng, Liu Xin, Wang Xiaozhuan, Sun Fengtian, Zhang Anbiao, Lu Xinya, Lin Yongzhi, Zhong Zhigang, Wang Xiaoshuai, Lin Chuangxin
Аннотация
OBJECTIVES: Osteoarthritis (OA) involves the structural failure of the joint unit, where the subchondral bone plate and associated vascular niche serve as a critical barrier and mechanical support for articular cartilage. This study investigates R-spondin 2 (Rspo2) as a mediator of instability within the subchondral bone plate-associated vascular niche and evaluates whether its pharmacological neutralization attenuates niche disruption and preserves osteochondral integrity.
METHOD: Human tibial-plateau subchondral bone scRNA-seq (GSE196678) and clinical specimens were analyzed to identify Wnt-related pathways. OA was induced in mice via ACLT + DMM surgery. Weekly intra-articular administration of recombinant Rspo2, an Rspo2-neutralizing antibody (Rspo2-NAb), or the Wnt inhibitor DKK1 began on postoperative day 3. Subchondral bone remodeling and cartilage degeneration were assessed in separate groups of mice at postoperative days 30 and 60.
RESULTS: The scRNA-seq analysis identified Wnt-related expression patterns in OA subchondral endothelial cells (ECs). Histology showed a higher percentage of CD31+/p-β-catenin (Ser675)+ cells in OA specimens than in controls. In vitro, rhRspo2 enhanced endothelial proliferation and tube formation, whereas conditioned medium from Rspo2-overexpressing ECs promoted osteogenic and osteoclastic differentiation and disrupted chondrocyte homeostasis; these effects were attenuated by Rspo2-NAb or DKK1, consistent with involvement of Wnt/β-catenin signaling. Early postoperative administration of Rspo2-NAb or DKK1 reduced subchondral bone plate remodeling and the proportion of CD31+EMCN+ cells, and attenuated cartilage degeneration in vivo.
CONCLUSIONS: These findings support a paracrine role for endothelial-derived Rspo2 in vitro and the potential of early Rspo2 neutralization to attenuate bone remodeling and cartilage degeneration in experimental OA.
METHOD: Human tibial-plateau subchondral bone scRNA-seq (GSE196678) and clinical specimens were analyzed to identify Wnt-related pathways. OA was induced in mice via ACLT + DMM surgery. Weekly intra-articular administration of recombinant Rspo2, an Rspo2-neutralizing antibody (Rspo2-NAb), or the Wnt inhibitor DKK1 began on postoperative day 3. Subchondral bone remodeling and cartilage degeneration were assessed in separate groups of mice at postoperative days 30 and 60.
RESULTS: The scRNA-seq analysis identified Wnt-related expression patterns in OA subchondral endothelial cells (ECs). Histology showed a higher percentage of CD31+/p-β-catenin (Ser675)+ cells in OA specimens than in controls. In vitro, rhRspo2 enhanced endothelial proliferation and tube formation, whereas conditioned medium from Rspo2-overexpressing ECs promoted osteogenic and osteoclastic differentiation and disrupted chondrocyte homeostasis; these effects were attenuated by Rspo2-NAb or DKK1, consistent with involvement of Wnt/β-catenin signaling. Early postoperative administration of Rspo2-NAb or DKK1 reduced subchondral bone plate remodeling and the proportion of CD31+EMCN+ cells, and attenuated cartilage degeneration in vivo.
CONCLUSIONS: These findings support a paracrine role for endothelial-derived Rspo2 in vitro and the potential of early Rspo2 neutralization to attenuate bone remodeling and cartilage degeneration in experimental OA.