Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis

Abstract

Osteoporosis is caused by pathologic factors such as aging, hormone deficiency or excess, inflammation, and systemic diseases like diabetes. Bone marrow stromal cells (BMSCs), the mesenchymal progenitors for both osteoblasts and adipocytes, are modulated by niche signals. In differential pathologic states, the pathological characteristics of BMSCs to osteoporoses and functional differences are unknown. Here, we detected that trabecular bone loss co-existed with increased marrow adiposity in 6 osteoporotic models, respectively induced by natural aging, accelerated senescence (SAMP6), ovariectomy (OVX), type 1 diabetes (T1D), excessive glucocorticoids (GIOP) and orchidectomy (ORX). Of the ex vivo characteristics of BMSCs, the colony-forming efficiency and the proliferation rate in aging, SAMP6, OVX, GIOP and ORX models decreased. The apoptosis and cellular senescence increased except in T1D, with up-regulation of p53 and p16 expression. The osteogenesis declined except in GIOP, with corresponding down-regulation of Runt-related transcription factor 2 (RUNX2) expression. The adipogenesis increased in 6 osteoporotic models, with corresponding up-regulation of Peroxisome proliferator activated receptor gamma (PPARγ) expression. These findings revealed differential characteristics of BMSCs in a common shift from osteoblastogenesis to adipogenesis among different osteoporoses and between sexes, and provide theoretical basis for the functional modulation of resident BMSCs in the regenerative therapy for osteoporosis.

Recipient Glycemic Micro-environments Govern Therapeutic Effects of Mesenchymal Stem Cell Infusion on Osteopenia

“…S2A-D), and were in accordance with surface profiles currently recognized to represent MSCs (Fig. S2E) 8, 23, 42. MSCs were infused at D25, at which time point hyperglycemia in T1D mice was stable around 400 mg/dL, as shown previously 25 and here by 3 consecutive quantifications (Fig.…”

“…MSCs were infused at D25, at which time point hyperglycemia in T1D mice was stable around 400 mg/dL, as shown previously 25 and here by 3 consecutive quantifications (Fig. S1A), and substantial bone loss was reported to occur in both OVX and T1D mice 23. Post infusion, flow cytometry demonstrated successful transplantation of donor MSCs into recipient circulation (Fig.…”

“…Blood GLU concentrations were quantified using a glucometer (Roche Bioproducts, Switzerland) following tail vein-puncture whole blood sampling 23. Mice with over 250 mg/dL GLU in blood were classified as diabetic or hyperglycemic 25.…”

DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age

“…In both humans and rodents, the reduced osteoblast number in the aging skeleton has been attributed to changes in bone marrow‐derived mesenchymal progenitors, including a decrease in the number of mesenchymal stem cells, defective proliferation/differentiation of progenitor cells, increased apoptosis, or increased senescence (Stenderup et al ., ; Sethe et al ., ). Studies using bone marrow‐derived stromal cells as a surrogate for osteoblast progenitors have suggested that serially passaged cells from aged humans or mice become senescence at earlier passages compared to cells from young individuals (Stenderup et al ., ; Zhou et al ., ; Sui et al ., ). However, serial passaging in and of itself causes replicative senescence (Hayflick & Moorhead, ) and bone marrow cell cultures are heterogeneous.…”

Redundant let‐7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis

“…Osteoporosis is closely related to dysfunction of BMSCs (39). Previous studies have revealed that osteoporotic BMSCs are defective in proliferation, multipotent differentiation, and osteoclast regulation (40). To our knowledge, this is the first study to report that the immune‐modulatory capacity of BMSCs also declined in osteoporosis.…”