Sonic Hedgehog Induces Mesenchymal Stromal Cell Senescence-Associated Secretory Phenotype and Chondrocyte Apoptosis in Human Osteoarthritic Cartilage

Abstract

Hedgehog (HH) signaling plays a critical role in osteoarthritis (OA) pathogenesis, but the molecular mechanism remains to be elucidated. We show here that Sonic Hedgehog (SHH) gene expression is initiated in human normal cartilage stromal cells (NCSC) and increased in OA cartilage mesenchymal stromal cells (OA-MSCs) during aging. Manifesting a reciprocal cellular distribution pattern, the SHH receptors PTCH1 and SMO and transcription factors GLI2 and GLI3 are expressed by chondrocytes (OAC) in OA cartilage. SHH autocrine treatment of osteoarthritis MSC stimulates proliferation, chondrogenesis, hypertrophy, and replicative senescence with elevated SASP gene expression including IL1B, IL6, CXCL1, and CXCL8. SHH paracrine treatment of OAC suppresses COL2A1, stimulates MMP13, and induces chondrocyte apoptosis. The OA-MSC conditioned medium recapitulates the stimulatory effects of SHH on OAC catabolism and apoptosis. SHH knock-down in OA-MSC not only inhibits catabolic and senescence marker expression in OA-MSC, but also abolishes the effect of the OA-MSC conditioned medium on OAC catabolism and apoptosis. We propose that SHH is a key mediator between OA-MSC and OA chondrocytes interaction in human OA cartilage via two mechanisms: (1) SHH mediates MSC growth and aging by activating not only its proliferation and chondrogenesis, but also low-grade inflammation and replicative senescence, and (2) SHH mediates OA-MSC-induced OAC catabolism and apoptosis by creating a pro-inflammatory microenvironment favoring tissue degeneration during OA pathogenesis.

Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration

“…This established the cell senescence pathway in cartilage from OAC to NCSC to OA-MSC. OA-MSC, the terminally senescent cells in cartilage, expressed high levels of SASPs including proinflammatory cytokines IL-1b, IL-6, IL-8, growth factor TGF-b1, and morphogen Sonic Hedgehog [ 20 , 29 ]. Interestingly, OAC expressed receptors for these signaling molecules [ 20 ].…”

“…An important consequence of senescence-associated cell transition is enabling heterotypic cell interaction between SnMSCs and non-senescent SomC. SASPs appear to be major signaling molecules mediating the SACTAI, as shown by recent publications [ 29 , 31 ]. The interaction between senescent and non-senescent cells is a two-way communication.…”

“…On the other hand, chondrocytes are the main recipient cells of inflammatory signaling by expressing IL-1R [ 20 ]. In addition to cytokine signaling, a recent study also identified Sonic Hedgehog (SHH) to mediate senescence signaling from snMSC to SomC [ 29 ]. SHH is known to play an important role during skeletal development and homeostasis [ 32 , 33 ].…”

“…SHH is known to play an important role during skeletal development and homeostasis [ 32 , 33 ]. SHH is expressed by NCSCs and increased in OA-MSCs during aging [ 29 ]. The SHH receptors (PTCH1 and SMO) and transcription factors (GLI2 and GLI3) are expressed by chondrocytes.…”

“…SHH paracrine treatment of OACs activated catabolic signaling in chondrocytes including suppressing anabolic ECM COL2A1 and increasing catabolic MMP13. Incubation of non-senescent OAC with the conditioned medium of senescent OA-MSC triggered massive cell death of OAC [ 29 ]. The senescence-triggered catabolism and apoptosis of non-senescent OAC depends on SHH, as SHH knock-down in OA-MSC abolishes its induction of chondrocyte death.…”