24Objective: Assess acute alterations in bone turnover, microstructure, and histomorphometry following 25 noninvasive anterior cruciate ligament rupture (ACLR). 26Methods: Twelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading 27 (n=6/group). In vivo μCT was performed at 3, 7, 10, and 14 days post-injury to quantify compartment-28 dependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near-infrared (NIR) molecular 29imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 30 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo 31 μCT and contrast-enhanced µCT, respectively. Calcein-based dynamic histomorphometry was used to 32 quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number 33 was quantified on TRAP stained-sections. 34Results: ACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal 35 compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days post-36 injury, while lateral femoral condyles (LFC) exhibited SCB gains. Trabecular thinning was observed in 37 MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and 38 sustained reduction of bone anabolism (~15-20%), and a ~32% increase in bone catabolism at 14 days, 39 compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and 40 increased osteoclast numbers, observed histologically. ACLR-injured femora had significantly elevated 41 OARSI score, cartilage thickness, and cartilage surface deviation. 42 Conclusion: ACL rupture induces immediate and sustained reduction of bone anabolism and 43 overactivation of bone catabolism, with mild-to-moderate articular cartilage damage at 14 days post-44 injury. 45 46 47 INTRODUCTION: 48 Post-traumatic osteoarthritis (PTOA) is a degenerative joint condition known to develop 49 following traumatic joint injuries. Anterior cruciate ligament (ACL) rupture is associated with a 50 particularly high risk for PTOA developmentapproximately 50% of patients develop PTOA 51 10-15 years after ACL rupture 1-3 . Surgical ACL reconstruction is a successful treatment to 52 alleviate pain and restore joint stability and function, but despite excellent patient-reported 53 outcomes and a high return-to-sport incidence, reconstruction has not been definitively shown to 54 alter the natural history of PTOA 2, 4, 5 . This observation has led to the hypothesis that acute 55 biological events initiated post-injury play a key role in the onset and progression of PTOA, as 56 opposed to primarily chronic joint instability. These biological events, their respective 57 contribution to PTOA pathogenesis, and the mechanisms that regulate them remain poorly 58 understood. 59 Crosstalk between articular cartilage (AC) and bone is an important component of 60 healthy joint homeostasis. AC and underlying bone interact via biochemical and mechanical 61...