Roles of apoptotic chondrocyte‐derived CXCL12 in the enhanced chondroclast recruitment following methotrexate and/or dexamethasone treatment

Abstract

Intensive use of methotrexate (MTX) and/or dexamethasone (DEX) for treating childhood malignancies is known to cause chondrocyte apoptosis and growth plate dysfunction leading to bone growth impairments. However, mechanisms remain vague and it is unclear whether MTX and DEX combination treatment could have additive effects in the growth plate defects. In this study, significant cell apoptosis was induced in mature ATDC5 chondrocytes after treatment for 48 h with 10−5 M MTX and/or 10−6 M DEX treatment. PCR array assays with treated cells plus messenger RNA and protein expression confirmation analyses identified chemokine CXCL12 having the most prominent induction in each treatment group. Conditioned medium from treated chondrocytes stimulated migration of RAW264.7 osteoclast precursor cells and formation of osteoclasts, and these stimulating effects were inhibited by the neutralizing antibody for CXCL12. Additionally, while MTX and DEX combination treatment showed some additive effects on apoptosis induction, it did not have additive or counteractive effects on CXCL12 expression and its functions in enhancing osteoclastic recruitment and formation. In young rats treated acutely with MTX, there was increased expression of CXCL12 in the tibial growth plate, and more resorbing chondroclasts were found present at the border between the hypertrophic growth plate and metaphysis bone. Thus, the present study showed an association between induced chondrocyte apoptosis and stimulated osteoclastic migration and formation following MTX and/or DEX treatment, which could be potentially or at least partially linked molecularly by CXCL12 induction. This finding may contribute to an enhanced mechanistic understanding of bone growth impairments following MTX and/or DEX therapy.

Cisplatin triggers oxidative stress, apoptosis and pro‐inflammatory responses by inhibiting the SIRT1‐mediated Nrf2 pathway in chondrocytes

“…8,26 For instance, it has been shown that intensive use of methotrexate or dexamethasone may lead to chondrocyte apoptosis along with osteoclastic migration and formation by induction of stromal cell-derived factor 1 (SDF-1). 26 Another study showed that radiation-induced ROS triggered cellular senescence and loss of type II collagen in chondrocytes via downregulation of SIRT1 by p38 kinase activation. 21 As an effective chemotherapy agent against several pediatric malignancies, cisplatin has been demonstrated to inhibit cell cycle progression, leading to cell loss of growth plate chondrocytes in vitro.…”

“…Accumulating evidence suggests that various cancer treatments or co‐medication for childhood malignancies cause chondrocyte apoptosis and growth plate dysfunction, which may result in growth impairments 8,26 . For instance, it has been shown that intensive use of methotrexate or dexamethasone may lead to chondrocyte apoptosis along with osteoclastic migration and formation by induction of stromal cell‐derived factor 1 (SDF‐1) 26 . Another study showed that radiation‐induced ROS triggered cellular senescence and loss of type II collagen in chondrocytes via downregulation of SIRT1 by p38 kinase activation 21 .…”

Senescence Induced by Nox4 Expressed Aberrantly in Osteoclast Precursors Accelerates Ostoeclastogenesis to Promote Osteoarthritis

“…The prior research into the intercellular signaling nd that a pathway for the osteoclast-chondrocyte crosstalk, described as pro-in ammatory factors released from subchondral bone like IL-1β 46 , TNF-α 47,48 , IL-6 49 and CXCL12 50,51 , regulates osteoclast differentiation. In addition, senescent chondrocytes produce pro-in ammatory SASP and catabolic enzymes potentially modulating the behavior of subchondral osteoclast lineage cells 52,53 .…”