Unraveling a novel mechanism of bone-cartilage crosstalk: the osteoclast-derived exosomal microRNAs promote cartilage degradation, osteochondral angiogenesis and innervation in early osteoarthritis

Project: Research project

Project Details


Osteoarthritis (OA) is the most common joint diseases worldwide. However, apart from purely symptomatic therapies, there are no medical interventions known to effectively prevent or delay the OA progression. A major reason for this rather desolate situation is the limited understanding of the molecular and cellular mechanisms underlying the pathogenesis, perpetuation and progression of OA. Pathologically, OA is a complex disease of the entire joint affecting bone, cartilage and synovium, of which the continuous articular cartilage (AC) degradation and aberrant subchondral bone (SCB) turnover are the two key pathological features of OA. Whether AC or SCB is the initiative tissue of OA is still contradictory since therapeutically targeting neither AC nor SCB showed promising effect on attenuating OA progression. Indeed, the AC and SCB are not only anatomically connected but also intimately interacted through bone-cartilage crosstalk. Therefore, it is highly desirable to investigate the regulatory mechanism directing the bone-cartilage crosstalk in OA.

Emerging evidence has implicated that exosomal microRNAs (miRNAs) could mediate the intercellular crosstalk either physiologically or under pathological conditions. However, the role of exosomal microRNAs in bone-cartilage crosstalk in OA development has not been elaborated. We have previously demonstrated that osteoclast-derived exosomal miRNAs could regulate osteoblastic bone formation, highlighting the crucial role of osteoclast-derived exosomal miRNAs in mediating the crosstalk between osteoclasts and other cell types. In our preliminary study on a mouse model with surgery-induced OA, we found that the elevated osteoclastic bone resorption at SCB of knee joint was accompanied by a series of upregulated miRNAs (including miR-214-3p, miR-30a-5p and miR-30b-5p) in CathepsinK-positive osteoclasts at SCB as well as serum exosomes in early OA development after anterior cruciate ligament transection (ACLT) surgery. Impressively, we observed that the OA progression, including AC degradation, osteochondral angiogenesis and innervation, was markedly retarded in mice lacking osteoclast-derived miRNAs (OCmiR-KO) as compared to the control mice with intact OCmiRs (OCmiR-Intact) at 28 days after ACLT. By in vitro studies, we further showed that the OCmiRs could traffic in exosomes to directly inhibit tissue inhibitor of metalloproteinases 2 (TIMP2) production in chondrocytes, therefore not only promote the catabolic activity of chondrocyte but also impair their resistance to angiogenesis and innervation. In addition, we observed the uptake of osteoclast-derived exosomes followed by the upregulated OCmiRs in AC chondrocytes of mice administered with PKH26-labelled osteoclast-derived exosomes. We also found that the levels of the OCmiRs in serum exosomes were markedly decreased after blockage of exosome secretion from osteoclasts in ACLT mice. Taken together, we hypothesized that the osteoclast-derived exosomal miRNAs could inhibit TIMP2 in chondrocytes to promote cartilage degradation, osteochondral angiogenesis and innervation in early OA development.

We have the following two specific aims for testing our hypothesis: (1) To investigate the effect of replenishing OCmiR-KO osteoclasts-derived exosomes (OCmiR-KO Exo) or OCmiR-Intact osteoclasts-derived exosomes (OCmiR-Intact Exo) on cartilaginous TIMP2 expression, AC degradation, osteochondral angiogenesis and innervation in the knee joint of OCmiR-KO mice in early OA development after ACLT. (2) To study the influence of disturbing exosome secretion from osteoclasts on cartilaginous TIMP2 expression, AC degradation, osteochondral angiogenesis and innervation in the knee joint of OCmiR-Intact mice in early OA development after ACLT.

The current proposal will unravel a novel mechanism of bone-cartilage crosstalk in early OA development. The findings are expected to facilitate developing new therapeutic strategy to prevent OA progression in future.
Effective start/end date1/01/2030/06/22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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