Abnormal subchondral bone remodeling plays important roles during osteoarthritis (OA) pathology. Recent studies show that bone marrow mesenchymal stem cells (BMSCs) in osteoarthritic subchondral bones exhibit a prominent pro-osteoclastic effect that contributes to abnormal subchondral bone remodeling; however, the pathologic mechanism remains unclear. In the present study, we used a mouse model with OA-like change in the temporomandibular joint (TMJ) induced by an experimentally unilateral anterior crossbite (UAC) and found that the level of microRNA-29b ( miR-29b), but not miR-29a or miR-29c, was markedly lower in BMSCs from subchondral bones of UAC mice as compared with that from the sham control mice. With an intra-articular aptamer delivery system, BMSC-specific overexpression of miR-29b by aptamer-agomiR-29b rescued subchondral bone loss and osteoclast hyperfunction in UAC mice, as demonstrated by a significant increase in bone mineral density, bone volume fraction, trabecular thickness, and the gene expression of osteocalcin and Runx2 but decreased trabecular separation, osteoclast number and osteoclast surface/bone surface, and the gene expression of cathepsin K, Trap, Wnt5a, Rankl, and Rank as compared with those in the UAC mice treated by aptamer-NC (all P < 0.05). In addition, BMSC-specific inhibition of miR-29b by aptamer-antagomiR-29b exacerbated those responses in UAC mice. Notably, although it primarily affected miR-29b levels in the subchondral bone (but not in cartilage and synovium), BMSC-specific overexpression of miR-29b in UAC mice largely rescued OA-like cartilage degradation, including decreased chondrocyte density, cartilage thickness, and the percentage areas of proteoglycans and type II collagen, while BMSC-specific inhibition of miR-29b aggravated these characteristics of cartilage degradation in UAC mice. Moreover, we identified Wnt5a, but not Rankl or Sdf-1, as the direct target of miR-29b. The results of the present study indicate that miR-29b is a key regulator of the pro-osteoclastic effects of BMSCs in TMJ-OA subchondral bones and plays important roles in the TMJ-OA progression.

Although deoxyribonucleic acid (DNA) is the genetic coding for the very essence of life, these macromolecules or components thereof are not necessarily lost after a cell dies. There appears to be a link between extracellular DNA and biomineralization. Here the authors demonstrate that extracellular DNA functions as an initiator of collagen intrafibrillar mineralization. This is confirmed with in vitro and in vivo biological mineralization models. Because of their polyanionic property, extracellular DNA molecules are capable of stabilizing supersaturated calcium phosphate solution and mineralizing 2D and 3D collagen matrices completely as early as 24 h. The effectiveness of extracellular DNA in biomineralization of collagen is attributed to the relatively stable formation of amorphous liquid droplets triggered by attraction of DNA to the collagen fibrils via hydrogen bonding. These findings suggest that extracellular DNA is biomimetically significant for fabricating inorganic-organic hybrid materials for tissue engineering. DNA-induced collagen intrafibrillar mineralization provides a clue to the pathogenesis of ectopic mineralization in different body tissues. The use of DNase for targeting extracellular DNA at destined tissue sites provides a potential solution for treatment of diseases associated with ectopic mineralization.

Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)–positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)–mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.

The periosteum orchestrates the microenvironment of bone regeneration, including facilitating local neuro-vascularization and regulating immune responses. To mimic the role of natural periosteum for bone repair enhancement, we adopted the principle of biomimetic mineralization to delicately inlay amorphous cerium oxide within eggshell membranes (ESMs) for the first time. Cerium from cerium oxide possesses unique ability to switch its oxidation state from cerium III to cerium IV and vice versa, which provides itself promising potential for biomedical applications. ESMs are mineralized with cerium­(III, IV) oxide and examined for their biocompatibility. Apart from serving as physical barriers, periosteum-like cerium­(III, IV) oxide-mineralized ESMs are biocompatible and can actively regulate immune responses and facilitate local neuro-vascularization along with early-stage bone regeneration in a murine cranial defect model. During the healing process, cerium-inlayed biomimetic periosteum can boost early osteoclastic differentiation of macrophage lineage cells, which may be the dominant mediator of the local repair microenvironment. The present work provides novel insights into expanding the definition and function of a biomimetic periosteum to boost early-stage bone repair and optimize long-term repair with robust neuro-vascularization. This new treatment strategy which employs multifunctional bone-and-periosteum-mimicking systems creates a highly concerted microenvironment to expedite bone regeneration.

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