Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis

Abstract

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2 , which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair

“…Aldh1a2 encodes an enzyme necessary for synthesis of all‐trans retinoic acid. Loss‐of‐function variants are associated with osteoarthritis and ALDH1A2 may be involved in suppressing mechanoflammation through increased synthesis of retinoic acid 37–39 . Our data support the hypothesis that activation of growth factor pathways and reduction of inflammation may be a key step the healing process after RCR.…”

Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair

“…Aldh1a2 encodes an enzyme necessary for synthesis of all‐trans retinoic acid. Loss‐of‐function variants are associated with osteoarthritis and ALDH1A2 may be involved in suppressing mechanoflammation through increased synthesis of retinoic acid 37–39 . Our data support the hypothesis that activation of growth factor pathways and reduction of inflammation may be a key step the healing process after RCR.…”

A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population

“…Several studies have suggested that altered retinoic acid signalling may contribute to the development and progression of OA (Davies et al., 2009; Hughes et al., 2016). In a recently published study, boosting all‐trans retinoic acid was found to suppress mechanoflammation in the articular cartilage, which reinforced the anti‐inflammatory role of retinoic acid (Zhu et al., 2022). In animal models, disruption of retinoic acid signalling has been shown to accelerate cartilage degeneration and OA‐like changes (Welch et al., 2009).…”

Metabolic profiling defines glioblastoma subtypes with distinct prognoses and therapeutic vulnerabilities

“… 17 Based on the distinct metabolic characteristics of each subtype, we selected three inhibitors: M-31850, which targets glycosaminoglycan degradation via HEX inhibition 41 ; FK866, a NAMPT inhibitor targeting nicotinate and nicotinamide metabolism 42 ; and Talarozole, a CYP26 inhibitor that disrupts retinoic acid metabolism. 43 These pathways showed relatively higher activity in the M3 subtype across both GBM tissue samples and PDCs ( Supplementary Figure 11A-C ). Consistently, expression of the respective target genes was elevated at both the mRNA and protein levels in M3 subtypes across multiple GBM and PDC cohorts ( Figure 6A-C , Supplementary Figure 11D ).…”

Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair

“…Aldh1a2 encodes an enzyme necessary for synthesis of all‐trans retinoic acid. Loss‐of‐function variants are associated with osteoarthritis and ALDH1A2 may be involved in suppressing mechanoflammation through increased synthesis of retinoic acid 37–39 . Our data support the hypothesis that activation of growth factor pathways and reduction of inflammation may be a key step the healing process after RCR.…”

A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population

“…Several studies have suggested that altered retinoic acid signalling may contribute to the development and progression of OA (Davies et al., 2009; Hughes et al., 2016). In a recently published study, boosting all‐trans retinoic acid was found to suppress mechanoflammation in the articular cartilage, which reinforced the anti‐inflammatory role of retinoic acid (Zhu et al., 2022). In animal models, disruption of retinoic acid signalling has been shown to accelerate cartilage degeneration and OA‐like changes (Welch et al., 2009).…”

Metabolic profiling defines glioblastoma subtypes with distinct prognoses and therapeutic vulnerabilities

“… 17 Based on the distinct metabolic characteristics of each subtype, we selected three inhibitors: M-31850, which targets glycosaminoglycan degradation via HEX inhibition 41 ; FK866, a NAMPT inhibitor targeting nicotinate and nicotinamide metabolism 42 ; and Talarozole, a CYP26 inhibitor that disrupts retinoic acid metabolism. 43 These pathways showed relatively higher activity in the M3 subtype across both GBM tissue samples and PDCs ( Supplementary Figure 11A-C ). Consistently, expression of the respective target genes was elevated at both the mRNA and protein levels in M3 subtypes across multiple GBM and PDC cohorts ( Figure 6A-C , Supplementary Figure 11D ).…”

Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair

“…Aldh1a2 encodes an enzyme necessary for synthesis of all‐trans retinoic acid. Loss‐of‐function variants are associated with osteoarthritis and ALDH1A2 may be involved in suppressing mechanoflammation through increased synthesis of retinoic acid 37–39 . Our data support the hypothesis that activation of growth factor pathways and reduction of inflammation may be a key step the healing process after RCR.…”

A functional variant of ALDH1A2 is associated with hand osteoarthritis in the Chinese population

“…Several studies have suggested that altered retinoic acid signalling may contribute to the development and progression of OA (Davies et al., 2009; Hughes et al., 2016). In a recently published study, boosting all‐trans retinoic acid was found to suppress mechanoflammation in the articular cartilage, which reinforced the anti‐inflammatory role of retinoic acid (Zhu et al., 2022). In animal models, disruption of retinoic acid signalling has been shown to accelerate cartilage degeneration and OA‐like changes (Welch et al., 2009).…”

Metabolic profiling defines glioblastoma subtypes with distinct prognoses and therapeutic vulnerabilities

“… 17 Based on the distinct metabolic characteristics of each subtype, we selected three inhibitors: M-31850, which targets glycosaminoglycan degradation via HEX inhibition 41 ; FK866, a NAMPT inhibitor targeting nicotinate and nicotinamide metabolism 42 ; and Talarozole, a CYP26 inhibitor that disrupts retinoic acid metabolism. 43 These pathways showed relatively higher activity in the M3 subtype across both GBM tissue samples and PDCs ( Supplementary Figure 11A-C ). Consistently, expression of the respective target genes was elevated at both the mRNA and protein levels in M3 subtypes across multiple GBM and PDC cohorts ( Figure 6A-C , Supplementary Figure 11D ).…”