Dynamic Balance between PTH1R-Dependent Signal Cascades Determines Its Pro- or Anti-Osteogenic Effects on MSC

Abstract

Parathyroid hormone (PTH) is one of the key regulators of calcium and phosphate metabolism in the body, controlling bone metabolism and ion excretion by the kidneys. At present, attempts to use PTH as a therapeutic agent have been associated with side-effects, the nature of which is not always clear and predictable. In addition, it is known that in vivo impairment of PTH post-receptor signaling is associated with atypical differentiation behavior not only of bone cells, but also of connective tissues, including adipose tissue. In this work, we studied the functional responses of multipotent mesenchymal stromal cells (MSCs) to the action of PTH at the level of single cells. We used MSCs isolated from the periosteum and subcutaneous adipose tissue to compare characteristics of cell responses to PTH. We found that the hormone can activate three key responses via its receptor located on the surface of MSCs: single transients of calcium, calcium oscillations, and hormone-activated smooth increase in intracellular calcium. These types of calcium responses led to principally different cellular responses of MSCs. The cAMP-dependent smooth increase of intracellular calcium was associated with pro-osteogenic action of PTH, whereas phospholipase C dependent calcium oscillations led to a decrease in osteogenic differentiation intensity. Different variants of calcium responses are in dynamic equilibrium. Suppression of one type of response leads to increased activation of another type and, accordingly, to a change in the effect of PTH on cell differentiation.

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

“…Conversely, PTH’s catabolic effect on SSCs is mediated by Ca2+ oscillations induced by PKC [ 69 ]. It is probable that PTH1R in SSCs engages in dynamic interactions with both Ca2+-dependent and cAMP-dependent signaling pathways, and the dominance of one pathway over the other determines the specific functional impact of PTH on these cells.…”

Noradrenaline and serotonin-dependent sensitization of MSCs to noradrenaline

“…Patients whose MSCs were able to show permissive action of monoamines to noradrenaline were identified by the fact that their MSCs increased their sensitivity to noradrenaline after preincubation with noradrenaline or 5-HT by 1.5 times or more. Trial registration: Not applicable Ethics: MSCs were isolated from subcutaneous fat tissue of analyzed donors using enzymatic digestion as previously described [3 , 7] . The work was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).…”

Editorial: Functional heterogeneity of stem cells

“…Secondly, stem cells of even the same type differ when they are isolated from different organs. For example, multipotent mesenchymal stromal cells (MSCs) of adipose tissue differ in their proliferative, and differentiation potential, as well as in their immunomodulatory ability when isolated from various adipose tissue depots (Kulebyakin et al, 2022). Further, stem cells are heterogeneous in their sensitivity to regulatory hormones.…”