WISP-2 expression induced by Teriparatide treatment affects in vitro osteoblast differentiation and improves in vivo osteogenesis

Abstract

The Osteocyte, recognized as a major orchestrator of osteoblast and osteoclast activity, is the most important key player during bone remodeling processes. Imbalances occurring during bone remodeling, caused by hormone perturbations or by mechanical loading alterations, can induce bone pathologies such as osteoporosis. Recently, the active fraction of parathormone, PTH (1-34) or Teriparatide (TPTD), was chosen as election treatment for osteoporosis. The effect of such therapy is dependent on the temporal manner of administration. The molecular reasons why the type of administration regimen is so critical for the fate of bone remodeling are numerous and not yet well known. Our study attempts to analyze diverse signaling pathways directly activated in osteocytes upon TPTD treatment. By means of gene array analysis, we found many molecules upregulated or downregulated in osteocytes. Later, we paid attention to Wisp-2, a protein involved in the Wnt pathway, that is secreted by MLO-Y4 cells and increases upon TPTD treatment and that is able to positively influence the early phases of osteogenic differentiation. We also confirmed the pro osteogenic property of Wisp-2 during mesenchymal stem cell differentiation into the preliminary osteoblast phenotype. The same results were confirmed with an in vivo approach confirming a remarkable Wisp-2 expression in metaphyseal trabecular bone. These results highlighted the anabolic roles unrolled by osteocytes in controlling the action of neighboring cells, suggesting that the perturbation of certain signaling cascades, such as the Wnt pathway, is crucial for the positive regulation of bone formation.

Bone on-a-chip: a 3D dendritic network in a screening platform for osteocyte-targeted drugs

“…However, to date, there are no ways to characterize a hydrogel when it is inside a microchannel. Thus, we performed rheological tests on the hydrogels used, and as expected, we found an elastic modulus between 10 and 100 Pa (supplementary figure 2(d)) which is considerably lower than the elastic module of human bone (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Therefore, we choose the hydrogel and the collagen concentrations based on the best solution that allowed for gel loading in the microfluidic device without exerting high shear stress on the cells during the loading, ensuring homogenous cell distribution within the gel and an appropriate cell viability over time, without considering the elastic modulus.…”

“…Meticulous studies in the past 15 years have prompted the development of innovative therapeutic agents that can treat these conditions, with an anabolic effect on bone, like antibodies against Sost (e.g. Romosozumab, Blosozumab) suggested for the treatment of osteoporosis [17], or teriparatide (PTH1-34) suggested for osteogenesis imperfecta and osteoporosis [18][19][20][21][22]. In particular, teriparatide has both an anabolic effect in osteoblasts and anti-apoptotic effects in Oc by targeting Wnt-1 inducible signalling pathway protein 2 and Sost signalling.…”

Combining single-cell transcriptomics and CellTagging to identify differentiation trajectories of human adipose-derived mesenchymal stem cells

“…We analyzed the differential genes of P15 cells. On the basis of differential gene expression, we identified that cluster CC5 mainly expressed the fibroblast-related genes MMP1 [ 30 ] and DCN [ 31 ]; cluster CC6 mainly expressed genes related to osteogenic differentiation regulation, such as JUN [ 34 ], Insulin Like Growth Factor Binding Protein 3 ( IGFBP3 ) [ 36 ], and Cellular Communication Network Factor 5 ( WISP2 ) [ 37 ]; cluster CC15 mainly expressed chondrocyte-related genes CHI3L1 [ 29 ], Matrix Gla Protein ( MGP ) [ 38 ], and CYP1B1 [ 28 ]; cluster CC0, CC4, CC8, and CC13 mainly expressed extracellular matrix-related genes; cluster CC9 expressed smooth muscle-related genes MYL6 [ 26 ], ACTA2 [ 25 ], and TPM2 [ 27 ]; and clusters CC1, CC2, CC3, and CC14 mainly expressed adipose-related genes, such as CCAAT Enhancer Binding Protein Beta ( CEBPB ) [ 39 ], EBF Transcription Factor 2 ( EBF2 ) [ 40 ], TAGLN [ 32 ], and HMGA2 (Fig. 4 A, B ) [ 33 ].…”

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

“…PTH is known to activate the canonical Wnt signaling pathway and boost the production of WISP2 specifically in osteocytes, leading to an enhancement of the mineralization process [ 194 ]. In addition, LRP6 serves as a co-receptor for various G protein-coupled seven-transmembrane receptors, like Wnt receptor FZD and PTH1R, and plays a role in the production of cAMP.…”