More and more evidences showed that cartilage harbored local progenitor cells that could differentiate toward osteoblast, chondrocyte, and adipocyte. However, our previous results showed that osteoarthritis derived chondroprogenitor cells (OA-CPC) exhibited strong osteogenic potential even in chondrogenic condition. How to promote their chondrogenic potential is the key for cartilage repair and regeneration in osteoarthritis. Recently, lipid availability was proved to determine skeletal progenitor fate. Therefore, we aim to determine whether lipid inhibition under 3D culture condition could enhance OA-CPC chondrogenesis. Moreover, glucose concentration was also evaluated for chondrogenic capacity. Although there are many researches showed that lower glucose promotes chondrogenesis, in our results, we found that OA-CPC in high concentration of glucose (4.5g/L) with lipid inhibitor (GW1100) showed strongest chondrogenic potential, which could form largest cell pellet with strong proteoglycan staining, COL II expression and no COL I expression. Besides, COL2A1 was increased and COL10A1 was decreased significantly by GW1100 under high glucose condition in 2D culture. Interestingly, although the expression level of MMP13 was not changed by GW1100 at RNA and protein level, less MMP13 protein secreted out of cell nuclear. In summary, we estimated that higher glucose and lower lipid supplies benefit OA-CPC chondrogenesis and cartilage repair.

Although remnant-preserved ACL reconstruction (ACLR) restores knee joint stability and dampens the problem of acute ACL rupture-induced knee pain, an increasing number of patients still develop post-traumatic osteoarthritis (PTOA) after 10 to 15 years of ACLR. We previously found that remnant-preserved ACLR with concomitant medial and lateral meniscus repair may not prevent cartilage degeneration and weaken muscle strength, while the clinical features of PTOA are not clear. We hypothesized that remnant-preserved ACLR with concomitant medial and lateral meniscus tears is related to early cartilage damage, worse function recovery, patient-reported outcomes (PROs) and delayed duration to return to sports. The aim is to evaluate the remnant-preserved ACLR with complicated meniscal injuries in predicting which patients are at higher risk of osteoarthritic changes, worse function and limited activities after ACLR for 12 months.

Human ethical issue was approved by a committee from Xi'an Jiaotong University. 26 young and active patients (24 male, 2 female) with ACL injuries (Sherman type I and II) with concomitant medial and lateral meniscus within 2 months were included from January 2014 to March 2022. The average age of the ACLR+ meniscus repair was 26.77±1.52 (8 right, 5 left) and isolated ACLR control was 31.92±2.61 years old (7 left, 6 right). Remnant-preserved ACLR with a 5- to 6-strand hamstring tendon graft was operated on by the same sports medicine specialists. MRI CUBE-T₂ scanning with 48 channels was conducted by a professional radiologist. The volume of the ACL graft was created through 3 dimensional MRI model (Mimics 19, Ann Arbor). Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS) was applied to score visible cartilage damage. IKDC 2000 score and VAS were assessed by two blinded researchers. Results were presented as mean± SEM of each group.

The cross-sectional area and 3D volume of the ACL graft were greater in the remnant-preserved ACLR+meniscus group compared with isolated ACLR (p=0.01). It showed that ACLR+ meniscus group had early signs of joint damage and delayed meniscus healing regarding ACLOAS compared to control group (p=0.045). MRI CUBE-T₂ prediction of radiographic cartilage degeneration was not obvious in both groups post remnant-preserved ACLR over 12 months (p>0.05). However, higher VAS scores, lower IKDC scores, and long-last joint swelling were reported in the ACLR+ meniscus repair group at the end of 12 months follow-up. Although remnant-preserved ACLR+ meniscus was able to maintain the restore the knee function, it showed delayed timing (>12 months) to return to play at the pre-injury stage, while no difference between the timing of returning to the normal daily routine of their ACLR knee compared to control (p=0.30). The cost of ACLR+ meniscus (average 10,520.76$) was higher than the control group (6,452.92$, p=0.018).

Remnants-preserved ACLR with concomitant injured medial and lateral meniscus repair shows a higher risk of cartilage damage, greater cost, worse functional performance, and longer time for young male patients to return to sports after 12-month follow-up compared to isolated ACLR. Further evidence and long-term follow-up are needed to better understand the association between these results and the risk of development of PTOA in this patient cohort.

Varus malalignment increases the susceptibility of cartilage to mechanical overloading, which stimulates catabolic metabolism to break down the extracellular matrix and lead to osteoarthritis (OA). The altered mechanical axis from the hip, knee to ankle leads to knee joint pain and ensuing cartilage wear and deterioration, which impact millions of the aged population. Stabilization of the remaining damaged cartilage, and prevention of further deterioration, could provide immense clinical utility and prolong joint function. Our previous work showed that high tibial osteotomy (HTO) could shift the mechanical stress from an imbalanced status to a neutral alignment. However, the underlying mechanisms of endogenous cartilage stabilization after HTO remain unclear. We hypothesize that cartilage-resident mesenchymal stem cells (MSCs) dampen damaged cartilage injury and promote endogenous repair in a varus malaligned knee. The goal of this study is to further examine whether HTO-mediated off-loading would affect human cartilage-resident MSCs' anabolic and catabolic metabolism. This study was approved by IACUC at Xi'an Jiaotong University. Patients with medial compartment OA (52.75±6.85 yrs, left knee 18, right knee 20) underwent open-wedge HTO by the same surgeons at one single academic sports medicine center. Clinical data was documented by the Epic HIS between the dates of April 2019 and April 2022 and radiographic images were collected with a minimum of 12 months of follow-up. Medial compartment OA with/without medial meniscus injury patients with unilateral Kellgren /Lawrence grade 3–4 was confirmed by X-ray. All incisions of the lower extremity healed well after the HTO operation without incision infection. Joint space width (JSW) was measured by uploading to ImageJ software. The Knee injury and Osteoarthritis Outcome Score (KOOS) toolkit was applied to assess the pain level. Outerbridge scores were obtained from a second-look arthroscopic examination. RNA was extracted to quantify catabolic targets and pro-inflammatory genes (QiaGen). Student's t test for two group comparisons and ANOVA analysis for differences between more than 2 groups were utilized. To understand the role of mechanical loading-induced cartilage repair, we measured the serial changes of joint space width (JSW) after HTO for assessing the state of the cartilage stabilization. Our data showed that HTO increased the JSW, decreased the VAS score and improved the KOOS score significantly. We further scored cartilage lesion severity using the Outerbridge classification under a second-look arthroscopic examination while removing the HTO plate. It showed the cartilage lesion area decreased significantly, the full thickness of cartilage increased and mechanical strength was better compared to the pre-HTO baseline. HTO dampened medial tibiofemoral cartilage degeneration and accelerate cartilage repair from Outerbridge grade 2 to 3 to Outerbridge 0 to 1 compared to untreated varus OA. It suggested that physical loading was involved in HTO-induced cartilage regeneration. Given that HTO surgery increases joint space width and creates a physical loading environment, we hypothesize that HTO could increase cartilage composition and collagen accumulation. Consistent with our observation, a group of cartilage-resident MSCs was identified. Our data further showed decreased expression of RUNX2, COL10 and increased SOX9 in MSCs at the RNA level, indicating that catabolic activities were halted during mechanical off-loading. To understand the role of cartilage-resident MSCs in cartilage repair in a biophysical environment, we investigated the differentiation potential of MSCs under 3-dimensional mechanical loading conditions. The physical loading inhibited catabolic markers (IL-1 and IL-6) and increased anabolic markers (SOX9, COL2).

Knee-preserved HTO intervention alleviates varus malalignment-related knee joint pain, improves daily and recreation function, and repairs degenerated cartilage of medial compartment OA. The off-loading effect of HTO may allow the mechanoregulation of cartilage repair through the differentiation of endogenous cartilage-derived MSCs.