CAMKK2 is upregulated in primary human osteoarthritis and its inhibition protects against chondrocyte apoptosis

Dilley, Julian E.; Seetharam, Abhijit; Ding, Xinchun; Bello, Margaret Anne; Shutter, Jennifer A.; Burr, David B.; Natoli, Roman M; McKinley, Todd O.; Sankar, Uma

doi:10.1016/j.joca.2023.02.072

Cited by 5 publications

(4 citation statements)

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“…A recent study highlighted the potential role of CaMKK2 in human primary OA [ 87 ] . Similar to observations from the mouse PTOA model, CaMKK2 mRNA and protein were elevated in human OA cartilage compared with paired intact cartilage from the same femoral head collected from total hip arthroplasty surgical discards.…”

Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

“…Similar to observations from the mouse PTOA model, CaMKK2 mRNA and protein were elevated in human OA cartilage compared with paired intact cartilage from the same femoral head collected from total hip arthroplasty surgical discards. Increased CaMKK2 was associated with increased expression of MMP-13 and decreased expression of anabolic markers COL2 and ACAN in the diseased cartilage [ 87 ] . Overexpression of intact CaMKK2 but not a functionally defective mutant in human chondrocytes elevated the levels of MMP-13, pSTAT3, and the pro-apoptotic marker BCL2 associated X (BAX), indicating that CaMKK2 enzyme activity is required for its role in coordinating inflammatory signaling in chondrocytes.…”

Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

“…Overexpression of intact CaMKK2 but not a functionally defective mutant in human chondrocytes elevated the levels of MMP-13, pSTAT3, and the pro-apoptotic marker BCL2 associated X (BAX), indicating that CaMKK2 enzyme activity is required for its role in coordinating inflammatory signaling in chondrocytes. Further, pharmacological inhibition of CaMKK2 activity suppressed chondrocyte death in OA cartilage explants [ 87 ] . Findings from this study indicate that CAMKK2 regulates catabolic and apoptotic responses in human primary chondrocytes, potentially through STAT3/MMP-13 and BAX-mediated mechanisms, further bolstering the status of CaMKK2 as a promising therapeutic target in the treatment of established primary OA, which currently has no clinical disease-modifying treatments.…”

Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

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Inflammatory mechanisms in post-traumatic osteoarthritis: a role for CaMKK2

Riggs,

Sankar

2023

Immunometabolism

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Post-traumatic osteoarthritis (PTOA) is a multifactorial disease of the cartilage, synovium, and subchondral bone resulting from direct joint trauma and altered joint mechanics after traumatic injury. There are no current disease-modifying therapies for PTOA, and early surgical interventions focused on stabilizing the joint do not halt disease progression. Chronic pain and functional disability negatively affect the quality of life and take an economic toll on affected patients. While multiple mechanisms are at play in disease progression, joint inflammation is a key contributor. Impact-induced mitochondrial dysfunction and cell death or altered joint mechanics after trauma culminate in inflammatory cytokine release from synoviocytes and chondrocytes, cartilage catabolism, suppression of cartilage anabolism, synovitis, and subchondral bone disease, highlighting the complexity of the disease. Current understanding of the cellular and molecular mechanisms underlying the disease pathology has allowed for the investigation of a variety of therapeutic strategies that target unique apoptotic and/or inflammatory processes in the joint. This review provides a concise overview of the inflammatory and apoptotic mechanisms underlying PTOA pathogenesis and identifies potential therapeutic targets to mitigate disease progression. We highlight Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/threonine protein kinase that was recently identified to play a role in murine and human osteoarthritis pathogenesis by coordinating chondrocyte inflammatory responses and apoptosis. Given its additional effects in regulating macrophage inflammatory signaling and bone remodeling, CaMKK2 emerges as a promising disease-modifying therapeutic target against PTOA.

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Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

Section: Camkk2 As a Therapeutic Target Against Oamentioning

confidence: 99%

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Inflammatory mechanisms in post-traumatic osteoarthritis: a role for CaMKK2

Riggs,

Sankar

2023

Immunometabolism

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“…OA is a multifactorial disease caused by genetics, joint trauma, aging, and obesity (Abramoff and Caldera 2020;Theeuwes et al 2021). OA severity is characterized by extracellular matrix (ECM) decomposition, chondrocyte apoptosis, synovitis, and subchondral bone pathology (Dilley et al 2023;Jiang et al 2020). It exerts a heavy burden on society and individuals (Hunter et al 2014;Martel-Pelletier et al 2016).…”

Section: Introductionmentioning

confidence: 99%

CHMP5 attenuates osteoarthritis via inhibiting chondrocyte apoptosis and extracellular matrix degradation: involvement of NF-κB pathway

Gao,

Liu,

Huang

et al. 2024

Mol Med

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Background Osteoarthritis (OA), the most common joint disease, is linked with chondrocyte apoptosis and extracellular matrix (ECM) degradation. Charged multivesicular body protein 5 (CHMP5), a member of the multivesicular body, has been reported to serve as an anti-apoptotic protein to participate in leukemia development. However, the effects of CHMP5 on apoptosis and ECM degradation in OA remain unclear. Methods In this study, quantitative proteomics was performed to analyze differential proteins between normal and OA patient articular cartilages. The OA mouse model was constructed by the destabilization of the medial meniscus (DMM). In vitro, interleukin-1 beta (IL-1β) was used to induce OA in human chondrocytes. CHMP5 overexpression and silencing vectors were created using an adenovirus system. The effects of CHMP5 on IL-1β-induced chondrocyte apoptosis were investigated by CCK-8, flow cytometry, and western blot. The effects on ECM degradation were examined by western blot and immunofluorescence. The potential mechanism was explored by western blot and Co-IP assays. Results Downregulated CHMP5 was identified by proteomics in OA patient cartilages, which was verified in human and mouse articular cartilages. CHMP5 overexpression repressed cell apoptosis and ECM degradation in OA chondrocytes. However, silencing CHMP5 exacerbated OA chondrocyte apoptosis and ECM degradation. Furthermore, we found that the protective effect of CHMP5 against OA was involved in nuclear factor kappa B (NF-κB) signaling pathway. Conclusions This study demonstrated that CHMP5 repressed IL-1β-induced chondrocyte apoptosis and ECM degradation and blocked NF-κB activation. It was shown that CHMP5 might be a novel potential therapeutic target for OA in the future.

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