Acetyl-11-keto-beta-boswellic acid ameliorates monosodium iodoacetate-induced osteoarthritis in rats: Implications of HMGB1/TLR4 /NF-κB, Nrf2/HO-1

Amira A El-gazar^1*Hagar Belal Abo-zalam¹Abdallah Mohammed¹Bassam Mohamed Ali¹Ghada M. Ragab²Heba Selim³Najat O. Hamed³Fatemah Alherz⁴Asmaa Saleh⁴Einas Yousef⁵

• ¹October 6 University, 6th of October City, Egypt
• ²Misr University for Science and Technology, 6th of October City, Egypt
• ³Almaarefa University, Riyadh, Saudi Arabia
• ⁴Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
• ⁵Alfaisal University, Riyadh, Saudi Arabia

Osteoarthritis (OA) is a prevalent joint disorder marked by chronic inflammation and degradation of cartilage. 3-O-Acetyl-11-keto-β-boswellic acid (AKBA) has certified its shielding effect in many inflammatory disorders. However, the full underlying mechanistic perspective of AKBA against OA remains unexplored. Thus, the objective of this work is to identify additional unexamined modulatory signals of AKBA against monosodium iodoacetate (MIA)-induced OA and earlier prevention of irreversible cartilage damage. Male Wistar rats were allotted into three groups (n = 9): Sham, MIA-OA, and MIA+AKBA250. Three mg of MIA were injected intra-articularly into the right knee joints of rats to induce OA on day zero. All treatments were given orally daily, starting on the 3rd day of MIA injection and continuing until the 14th day of the experiment. AKBA250 treatment alleviated edema completely, achieving nearly basal records of the right knee diameter. AKBA250 treatment enhanced macroscopic and microscopic findings and normalized Modified Mankin and OARSI scoring system. Moreover, AKBA restored cartilage matrix homeostasis by suppressing the catabolic enzyme MMP13, upregulating TIMP1 and the chondrogenic marker SOX9, and reducing the serum level of the cartilage degradation biomarker CTX-II. The contents of HMGB1, TLR4, NF-κB, and TNF-α were substantially suppressed in the AKBA250-treated group. AKBA250 significantly boosted Nrf2 and HO-1 levels and restored the oxidant/antioxidant equilibrium disrupted by MIA. In addition, AKBA250 prominently curbed the protein expression of pRIPK1, pRIPK3, and pMLKL. Further, AKBA250 exhibited downregulation of miR-34a-5p and miR-146a expressions. Together, AKBA demonstrated a protective function in OA by inhibiting inflammatory signaling through the HMGB1/TLR4/NF-κB pathway, augmenting the cytoprotective Nrf2/HO-1 pathway, and regulating necroptosis signaling cascades.