Abnormal subchondral bone remodeling and its association with articular cartilage degradation in knees of type 2 diabetes patients

Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.

Warming moxibustion attenuates inflammation and cartilage degradation in experimental rabbit knee osteoarthritis

OBJECTIVE:To explore the molecular mechanism of warming moxibustion(WM)in knee osteoarthritis(KOA).METHODS:The knee joints of 40 New Zealand rabbits were placed in a plaster cast in an extended position to establish a KOA model.The animals were randomly divided into four groups:the control group,model group,WM group,and diclofenac(DF)group.Hematoxylin-eosin staining and the modified Mankin score were applied to evaluate the histopathological changes.Chondrocyte apoptosis was determined by the terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay.Western blotting and real-time quantitative polymerase chain reaction were performed to measure the expression of interleukin-1β(IL-1β),prostaglandin E receptor 3(PTGER3),a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs-5(ADAMTS-5),matrix metalloproteinase-13(MMP-13),and C-terminal telopeptides of collagen typeⅡ(CTX-Ⅱ)in cartilage tissues of the different groups.The concentrations of IL-1β,PTGER3,and CTX-Ⅱin serum were detected by the enzyme-linked immunosorbent assay.RESULTS:Rabbits with KOA in the WM and DF groups showed significantly reduced cartilage erosion and Mankin scores,compared with the untreated rabbits.The number of TUNEL-positive cells observed in the WM group was much fewer than that in the model group.The expression of PTGER3,MMP-13,CTX-Ⅱ,IL-1β,and ADAMTS-5 in cartilage tissues was remarkably downregulated following therapy with WM and DF.Moreover,a marked reduction was observed in the serum levels of IL-1β,PTGER3,and CTX-Ⅱin the WM and DF groups.CONCLUSION:WM exerts favorable therapeutic effects on articular injuries of KOA by regulating the expression of inflammatory and cartilage degradation-related cytokines.

Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported.Here,we report that SHP099,as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2(SHP2),attenuated osteoarthritis progression by inhibiting M1 macrophage polarization.We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice.Compared to wild-type(WT)mice,myeloid lineage conditional Shp2 knockout(c KO)mice showed decreased M1 macrophage polarization and attenuated severity of synovitis,an elevated expression of cartilage phenotype protein collagen II(COL2),and a decreased expression of cartilage degradation markers collagen X(COL10)and matrix metalloproteinase3(MMP3)in OA cartilage.Further mechanistic analysis showed that SHP099 inhibited lipopolysaccharide(LPS)-induced Toll-like receptor(TLR)signaling mediated by nuclear factor kappa B(NF-κB)and PI3K—AKT signaling.Moreover,intra-articular injection of SHP099 also significantly attenuated OA progression,including joint synovitis and cartilage damage.These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.