Ruboxistaurin maintains the bone mass of subchondral bone for blunting osteoarthritis progression by inhibition of osteoclastogenesis and bone resorption activity

Pang, Cong; Wen, Liangbao; Lu, Xuanyuan; Luo, Shanchao; Qin, Haikuo; Zhang, Xuehui; Zhu, Bikang; Luo, Sulan

doi:10.1016/j.biopha.2020.110650

Cited by 7 publications

(3 citation statements)

References 37 publications

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“…This interaction occurs with a soluble fibronectin fragment generated from the proteolytic cleavage of the full-length protein [108,109]. Subsequently, this cascade triggers a significant activation of PKCδ, which in turn induces the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), eliciting a complex cellular response [110][111][112]. The NF-κB pathway stands as a potent proinflammatory agent, exerting significant influence in the initiation of OA.…”

Section: Pathogenesismentioning

confidence: 99%

Osteoarthritis: Insights into Diagnosis, Pathophysiology, Therapeutic Avenues, and the Potential of Natural Extracts

Coppola,

Greco,

Munir

et al. 2024

CIMB

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Osteoarthritis (OA) stands as a prevalent and progressively debilitating clinical condition globally, impacting joint structures and leading to their gradual deterioration through inflammatory mechanisms. While both non-modifiable and modifiable factors contribute to its onset, numerous aspects of OA pathophysiology remain elusive despite considerable research strides. Presently, diagnosis heavily relies on clinician expertise and meticulous differential diagnosis to exclude other joint-affecting conditions. Therapeutic approaches for OA predominantly focus on patient education for self-management alongside tailored exercise regimens, often complemented by various pharmacological interventions primarily targeting pain alleviation. However, pharmacological treatments typically exhibit short-term efficacy and local and/or systemic side effects, with prosthetic surgery being the ultimate resolution in severe cases. Thus, exploring the potential integration or substitution of conventional drug therapies with natural compounds and extracts emerges as a promising frontier in enhancing OA management. These alternatives offer improved safety profiles and possess the potential to target specific dysregulated pathways implicated in OA pathogenesis, thereby presenting a holistic approach to address the condition’s complexities.

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Section: Pathogenesismentioning

confidence: 99%

Osteoarthritis: Insights into Diagnosis, Pathophysiology, Therapeutic Avenues, and the Potential of Natural Extracts

Coppola,

Greco,

Munir

et al. 2024

CIMB

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“…Furthermore, they suggested that changes in the density and architecture of the underlying SB have a profound effect on both the initiation and progression of cartilage degeneration [6,7]. In addition, several animal studies have shown that SB loss can occur in the early stage of KOA and that the inhibition of bone resorption can suppress the progression of experimental KOA [8][9][10][11][12][13][14][15]. Bellido et al reported that microstructure impairment in the tibial SB associated with increased bone remodeling aggravated cartilage damage in rabbit KOA with previous osteoporosis (OP) [13].…”

Section: Introductionmentioning

confidence: 99%

Early subchondral bone loss plays an important role in initiation and progression of osteoarthritis in the mouse DMM model

Hashimoto

Akagi

Hashimoto

et al. 2023

Preprint

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Introduction: Recently, uncoupled bone remodeling in the subchondral bone (SB) has been considered an important process to promote knee osteoarthritis (KOA). However, it is unclear how SB metabolism in the early stage of KOA affects the initiation and progression of the disease. This study aimed to investigate the relationship between the early changes in SB and the disease process, using wild-type (WT) mice and Tsukuba hypertensive mice (THM) with high-turnover bone metabolism. Methods Destabilization of the medial meniscus (DMM) or sham surgery was performed on the left knee of male 40-week-old THM and WT mice (n = 7 in each group). Bone volume/tissue volume (BV/TV), bone mineral density (BMD), and mean height (Hm, µm) in the medial tibial SB were longitudinally measured in vivo using micro-computed tomography (µCT) at 0, 1, 2, 4, 8, and 12 weeks postoperatively. Tibial cartilage degeneration was evaluated histologically using the OARSI score at 0, 1, 2, 4, 8, and 12 weeks postoperatively (n = 7 in each group). Results Significant decreases in BV/TV in both WT + DMM and THM + DMM groups were evident at 1 and 4 weeks postoperatively, respectively. Notably, significant decreases in the BMD (at 2 and 8 weeks postoperatively) and Hm (at 4 and 12 weeks postoperatively), and significant increases in the Osteoarthritis Research Society International (OARSI) score (at 2 and 8 weeks postoperatively) in the THM + DMM and WT + DMM groups were observed, respectively. A strong correlation was noted between the Hm and the BMD. These time-dependent changes in the BV/TV, BMD, Hm in the SB, and OARSI score were significantly enhanced in the THM + DMM group compared to the WT + DMM group. Conclusions These results indicate that SB loss at the early stage and the subsequent uncoupled bone remodeling, which can be enhanced by high-turnover osteoporosis, play an important role in the initiation and progression of KOA in the mouse DMM model. SB loss in the early stage could be a key target for preventing the initiation and progression of the disease.

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“…Recent studies have demonstrated that the early loss of subchondral bone may further cause alterations in joint shape and load transmission that predispose patients to progressive cartilage degeneration (9)(10)(11). In addition, OA therapeutics targeting subchondral bone and preventing bone mass loss have exhibited significant efficacies for treating OA, suggesting an important role of subchondral bone in the development of OA (12)(13)(14)(15)(16). However, the mechanisms underlying bone turnover remain unclear, especially in early-stage OA.…”

Section: Introductionmentioning

confidence: 99%

Increased joint loading induces subchondral bone loss of the temporomandibular joint via the RANTES-CCRs-Akt2 axis

Feng¹,

Lei²,

Li³

et al. 2022

JCI Insight

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Early-stage temporomandibular joint osteoarthritis (TMJOA) is characterized by excessive subchondral bone loss. Emerging evidence suggests that TMJ disc displacement is involved, but the pathogenic mechanism remains unclear.Here, we established a rat model of TMJOA that simulated disc displacement and a capacitance-based force sensing system to directly measure articular surface pressure in vivo. Micro-CT, histological staining, immunofluorescence staining, immunohistochemistry staining, and Western blot were used to assess pathological changes and underlying mechanism of TMJOA in the rat model in vivo as well as in RAW264.7 cells in vitro. We found that disc displacement led to significantly higher pressure on articular surface, which caused subchondral bone loss rapidly via activation of RANTES-CCRs-Akt2 axis. Inhibition of RANTES or Akt2 attenuated subchondral bone loss and resulted in improved subchondral bone microstructure. Cytological studies substantiated that RANTES regulated osteoclast formation by binding to its receptor CCRs and activating Akt2 pathway. The clinical evidence further supported that RANTES was a potential biomarker for predicting subchondral bone loss in early-stage TMJOA. Taken together, this study demonstrates important functions of RANTES-CCRs-Akt2 axis in the regulation of subchondral bone remodeling and provides further knowledge of how disc displacement causes TMJOA.

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Ruboxistaurin maintains the bone mass of subchondral bone for blunting osteoarthritis progression by inhibition of osteoclastogenesis and bone resorption activity

Cited by 7 publications

References 37 publications

Osteoarthritis: Insights into Diagnosis, Pathophysiology, Therapeutic Avenues, and the Potential of Natural Extracts

Osteoarthritis: Insights into Diagnosis, Pathophysiology, Therapeutic Avenues, and the Potential of Natural Extracts

Early subchondral bone loss plays an important role in initiation and progression of osteoarthritis in the mouse DMM model

Increased joint loading induces subchondral bone loss of the temporomandibular joint via the RANTES-CCRs-Akt2 axis

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