To examine whether the defective response of PLS3 KD cells to substrates with different stiffnesses is linked to its actin-regulatory activity, and possibly to its role in early onset osteoporosis, we made use of three PLS3 point mutants that were identified in patients and that were recently shown to display defects in their calcium-sensitive actin-bundling activity, namely, PLS3 A368D, PLS3 N446S and PLS3 L478P (Schwebach et al., 2020). Here, PLS3 is linked to osteoporosis.