Glycogen synthase kinase 3 alpha/beta deletion induces precocious growth plate remodeling in mice.

Glycogen synthase kinase (GSK) 3 acts to negatively regulate multiple signaling pathways, including canonical Wnt signaling. The two mammalian GSK3 proteins (alpha and beta) are at least partially redundant. While Gsk3a KO mice are viable and display a metabolic phenotype, abnormal neuronal development, and accelerated aging, Gsk3b KO animals die late in embryogenesis or at birth. Selective Gsk3b KO in bone delays development of some bones, whereas cartilage-specific Gsk3b KO mice are normal except for elevated levels of GSK3A protein. However, the collective role of these two GSK3 proteins in cartilage was not evaluated. To address this, we generated tamoxifen-inducible, cartilage-specific Gsk3a/Gsk3b KO (described as "cDKO") in juvenile mice and investigated their skeletal phenotypes. We found that cartilage-specific Gsk3a/Gsk3b deletion in young, skeletally immature mice causes precocious growth plate (GP) remodeling, culminating in shorter long bones and hence, growth retardation. These mice exhibit inefficient breathing patterns at later stages and fail to survive. The disrupted GP in cDKO mice showed progressive loss of cellular and proteoglycan components, and immunostaining for SOX9, while BGLAP (osteocalcin) and COL2A1 increased. In addition, we observed increased osteoclast recruitment and cell apoptosis. Surprisingly, changes in articular cartilage of cDKO mice were mild compared with the GP, signifying differential regulation of articular cartilage vs GP tissues. Taken together, these findings emphasize a crucial role of two GSK3 proteins in skeletal development, in particular in the maintenance and function of GP. KEY MESSAGES: • Both GSK3 genes, together, are crucial regulators of growth plate remodeling. • Cartilage-specific deletion of both GSK3 genes causes skeletal growth retardation. • Deletion of both GSK3 genes decreases Sox9 levels and promotes chondrocyte apoptosis. • Cartilage-specific GSK3 deletion in juvenile mice culminates in premature lethality. • GSK3 deletion exhibits mild effects on articular cartilage compared to growth plate.

Expansion of myeloid-derived suppressor cells contributes to metabolic osteoarthritis through subchondral bone remodeling.

BACKGROUND: Osteoarthritis (OA) subsequent to acute joint injury accounts for a significant proportion of all arthropathies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells classically known for potent immune-suppressive activity; however, MDSCs can also differentiate into osteoclasts. In addition, this population is known to be expanded during metabolic disease. The objective of this study was to determine the role of MDSCs in the context of OA pathophysiology. METHODS: In this study, we examined the differentiation and functional capacity of MDSCs to become osteoclasts in vitro and in vivo using mouse models of OA and in MDSC quantitation in humans with OA pathology relative to obesity status. RESULTS: We observed that MDSCs are expanded in mice and humans during obesity. MDSCs were expanded in peripheral blood of OA subjects relative to body mass index and in mice fed a high-fat diet (HFD) compared to mice fed a low-fat diet (LFD). In mice, monocytic MDSC (M-MDSC) was expanded in diet-induced obesity (DIO) with a further expansion after destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA (PTOA) (compared to sham-operated controls). M-MDSCs from DIO mice had a greater capacity to form osteoclasts in culture with increased subchondral bone osteoclast number. In humans, we observed an expansion of M-MDSCs in peripheral blood and synovial fluid of obese subjects compared to lean subjects with OA. CONCLUSION: These data suggest that MDSCs are reprogrammed in metabolic disease, with the potential to contribute towards OA progression and severity.