Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis

Ginnetti, Anthony T.; Paone, Daniel V.; Nanda, Kausik K.; Li, Jing; Busuek, Marina; Johnson, Scott Allen; Lü, Jun; Soisson, S.M.; Robinson, R.; Fisher, John W.; Webber, Andrea L.; Wesolowski, Gregg; Ma, Bennett; Duong, Le T.; Carroll, Steven S.; Burgey, Christopher S.; Stachel, Shawn J.

doi:10.1016/j.bmcl.2022.128927

Cited by 7 publications

(4 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been found that cathepsin F can regulate the expression of multiple genes in the apoptosis pathway, such as enhancing the expression of pro-apoptotic gene Bid, while suppressing the expression of anti-apoptotic genes Bcl-2 and C-IAPs (28). In stem cell research, inhibition of cathepsin F demonstrates anti-apoptotic effects (29). Another study found that silencing the expression of cathepsin F enhances the growth of gastric cancer cells and reduces the level of cell apoptosis, thus promoting cancer progression; conversely, upregulation of cathepsin F expression has an inhibitory effect on cancer progression (30,31).…”

Section: Discussionmentioning

confidence: 99%

“…cathepsin F may be involved in the degradation process of articular cartilage in osteoarthritis. In osteoarthritis, articular cartilage is affected by various in ammatory and degenerative changes, including an increase in the activity of cathepsins (32). These cathepsins can degrade the matrix components of articular cartilage, such as collagen and proteoglycans, leading to cartilage destruction and degradation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mendelian randomization analysis explores the causal relationship between cathepsins and osteoarthritis

Huang,

Zhang,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

Osteoarthritis, a primary etiology of joint dysfunction, entails a multifaceted pathogenesis. Cathepsins, cysteine proteases localized within lysosomes, exert pivotal roles across diverse physiological and pathological contexts. Although observational inquiries suggest an interrelation between cathepsins and osteoarthritis, the etiological nexus remains elusive. Employing Mendelian randomization analysis, this investigation endeavors to elucidate this causal nexus. Univariate Mendelian randomization analysis reveals a plausible augmentation in osteoarthritis risk concomitant with a decline in cathepsin S levels. Conversely, reverse Mendelian randomization analysis posits that osteoarthritis might precipitate a reduction in cathepsin L2 levels. Multivariable analysis, encompassing 9 proteases as covariates, demonstrates a potential collaborative effect between elevated cathepsin F levels and diminished cathepsin S levels, thereby accentuating osteoarthritis risk. In summation, cathepsin S emerges as a prospective biomarker for osteoarthritis, conferring implications for diagnostic and therapeutic paradigms targeting this ailment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mendelian randomization analysis explores the causal relationship between cathepsins and osteoarthritis

Huang,

Zhang,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In recent years, novel classes of disease-modifying osteoarthritis drugs (DMOADs) have been developed, such as sprifermin [ 3 ], strontium ranelate [ 4 ], cathepsin K inhibitors [ 5 ], and MMP (matrix metalloproteinase) inhibitors [ 6 ]. Unlike conventional OA treatments, primarily involving symptom management, DMOADs aim to modulate the underlying pathophysiology of OA to preserve joint structure and function over time by slowing cartilage degradation.…”

Section: Introductionmentioning

confidence: 99%

Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

Hu,

Williams,

Palladino

et al. 2024

Polymers

View full text Add to dashboard Cite

Osteoarthritis (OA) is a chronic joint disease characterized by irreversible cartilage degradation. Current clinical treatment options lack effective pharmaceutical interventions targeting the disease's root causes. MMP (matrix metalloproteinase) inhibitors represent a new approach to slowing OA progression by addressing cartilage degradation mechanisms. However, very few drugs within this class are in preclinical or clinical trial phases. Hydrogel-based 3D in vitro models have shown promise as preclinical testing platforms due to their resemblance to native extracellular matrix (ECM), abundant availability, and ease of use. Metalloproteinase-13 (MMP-13) is thought to be a major contributor to the degradation of articular cartilage in OA by aggressively breaking down type II collagen. This study focused on testing MMP-13 inhibitors using a GelMA-alginate hydrogel-based OA model induced by cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The results demonstrate a significant inhibition of type II collagen breakdown by measuring C2C concentration using ELISA after treatment with MMP-13 inhibitors. However, inconsistencies in human cartilage explant samples led to inconclusive results. Nonetheless, the study highlights the GelMA-alginate hydrogel-based OA model as an alternative to human-sourced cartilage explants for in vitro drug screening.

show abstract

“…Cathepsin K, which is implicated in OA, and other arthritic diseases and osteoporosis, cleaves type II collagen at multiple sites [ 33 , 34 ]. Its clinical utility has been recognized, as cathepsin K inhibitors are indicated as a possible treatment for OA [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Compounds: Potential Therapeutics for the Inhibition of Cartilage Matrix Degradation in Osteoarthritis

Ashruf

Ansari

2022

Life

View full text Add to dashboard Cite

Osteoarthritis (OA) is the most common degenerative joint disease characterized by enzymatic degradation of the cartilage extracellular matrix (ECM) causing joint pain and disability. There is no disease-modifying drug available for the treatment of OA. An ideal drug is expected to stop cartilage ECM degradation and restore the degenerated ECM. The ECM primarily contains type II collagen and aggrecan but also has minor quantities of other collagen fibers and proteoglycans. In OA joints, the components of the cartilage ECM are degraded by matrix-degrading proteases and hydrolases which are produced by chondrocytes and synoviocytes. Matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS5) are the major collagenase and aggrecanase, respectively, which are highly expressed in OA cartilage and promote cartilage ECM degradation. Current studies using various in vitro and in vivo approaches show that natural compounds inhibit the expression and activity of MMP-13, ADAMTS4, and ADAMTS5 and increase the expression of ECM components. In this review, we have summarized recent advancements in OA research with a focus on natural compounds as potential therapeutics for the treatment of OA with emphasis on the prevention of cartilage ECM degradation and improvement of joint health.

show abstract

Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis

Cited by 7 publications

References 12 publications

Mendelian randomization analysis explores the causal relationship between cathepsins and osteoarthritis

Mendelian randomization analysis explores the causal relationship between cathepsins and osteoarthritis

Screening of MMP-13 Inhibitors Using a GelMA-Alginate Interpenetrating Network Hydrogel-Based Model Mimicking Cytokine-Induced Key Features of Osteoarthritis In Vitro

Natural Compounds: Potential Therapeutics for the Inhibition of Cartilage Matrix Degradation in Osteoarthritis

Contact Info

Product

Resources

About