Sex-dependent variation in bone adaptation: from degeneration to regeneration

Abstract

While known sex differences in bone health exist, scientific studies on bone degeneration and regeneration frequently disregard sex impact as a variable in outcomes. Evidence has established a higher risk of osteoporosis and increased bone degradation rates in women when compared to men. Accumulating research suggests that this disparity is also present in bone regeneration and repair. However, no comprehensive review highlighting the influence of sex currently exists in this field. This paper aims to review the information presently available on the cellular mechanisms behind skeletal sexual dimorphism specific to hormones and bone's degenerative and regenerative sex differences. This review will discuss the optimization of personalized regenerative therapies accounting for sex. The review emphasizes that sex impact must further be investigated to advance the field of bone regeneration and improve patient outcomes and quality of life. As translational medicine is JOT's focus, authors must highlight the translational potential or clinical significance of their work in both the abstract and the discussion. To this effect, it is required to include a statement following the abstract (included in the abstract word count) under the following heading: "The Translational Potential of this Article". 2. Please re-edit the reference list according to the following guidelines: 1) The last names and initials of all the authors up to 6 should be included, but when authors number 7 or more, list the first 6 authors only followed by 'et al'; 2) The "[eng]" in the reference list should be removed (if any); 3) Reference to a standard journal article (Please pay particular attention to the formatting, word capitalization, spacing and style): "Niemansburg SL, van Delden JJ, Dhert WJ, Bredenoord AL. Regenerative medicine interventions for orthopedic disorders: ethical issues in the translation into patients. Regen Med 2013;8:65-73.

Keywords: Bone; Degeneration; Hormone; Regeneration; Sex; Stem cell therapy.

Graphical abstract

Fig. 1

Hormone effects on skeletal sexual dimorphism. Estrogen:in females (left, light green), estrogens play a crucial role in promoting trabecular bone (TB) and cortical bone (CB) development and maintaining bone mineral density (BMD). ERα (estrogen receptor) is more prevalent in CB, while ERβ is more prevalent in TB [29]. ERα actions are crucial in promoting TB formation and inhibiting TB resorption as well as promoting CB [19,35]. ERβ could inhibit CB formation [36]. Estrogen also inhibits periosteal bone (PB) growth [33] and parathyroid hormone (PTH)-induced bone resorption [81]. In males (right, light green), estrogens play a crucial role in promoting TB, CB, and PB development and maintaining BMD maintenance via ERα. ERα may suppress TB volume [37]. ERβ does not play a significant role in the male skeleton [37,78]. The conversion of androgens into estrogen by P450 aromatase is a key process for male skeleton maintenance [43,65]. Androgen: in females (left, rose red), androgens play a crucial role in promoting bone formation and maintaining BMD [13,45]. Androgen receptors (ARs) have a crucial direct function in TB and CB maintenance in bone resorption and growth [46]. In males (right, rose red), ARs regulate TB, CB, and PB formation [53,54] and maintain BMD [60,61]. Growth hormone (GH): in females (left, pale pink), healthy females secrete more GH than males and GH deficiency is associated with lower insulin-like growth factor I (IGF-I) [[74], [75], [76]]. GH increases bone growth and strength and protects against bone loss [71,77]. In males (right, brown), healthy males secrete less GH than females. GH also increases bone growth and strength and protects against bone loss in males via stimulating IGF-I [71,77]. IGF-I: in females (left, orange), serum IGF-I levels are lower than in males and play a crucial role in bone mass formation [21]. In males (right, orange), IGF-I has a similar function as in females. ERα knockout (ERαKO) also decreased IGF-I levels in male mice, but ERβKO had no effect [37,78]. PTH: in females (left, pale purple), high levels of PTH have catabolic effects on the skeleton; however, low levels have an anabolic effect [80]. In males (right, pale purple), suppression of estrogen, testosterone, or both leads to increased skeletal responsiveness to the bone-resorbing effects of PTH in men [83,84].

Fig. 2

Cellular mechanisms of hormones and their effect on bone maintenance. TGFβ signaling pathway (a): Estrogen (E) and androgen (A) favor expression of TGFβ, which regulates the expression of BGLAP, OPN, ALPL, COL1A1, RUNX2, and BMP2 [31,54,94,95,97,98]. TGFβ3 inhibits the production of IL-1 and TNF of T-cells, which increases osteoclast differentiation by promoting RANKL expression [93]. TGFβ3 also inhibits RANKL signaling by increasing OPG expression [93]. OPG/RANKL signaling pathway (b): E and A enhance production of OPG from osteoblasts [116]. OPG binds to RANKL, blocking the activation of RANKL [107]. Without OPG, activation of RANKL would lead to recruitment of TRAF6, which has several downstream effects including activation of the MAPK and NF-κB pathways, which enables the expression of the ACP5, CTSK, and MMP9 genes [[233], [234], [235]]. TNF augments RANKL-induced osteoclastogenesis [236]. The activation of RANK by RANKL also leads to the production of ROS by osteoclast precursors via a signaling cascade involving TRAF6, [109]. ROS acts as an intracellular signal for the differentiation of osteoclast precursors into osteoclasts via MAPK and NF-κB pathways [108,115]. Wnt/β-catenin signaling pathway (c): Association of the Wnt molecule with FZD and LRP 5/6 leads to the release of β-catenin into the cytosol, which permits the transcription of OPG, promoting osteoblast activity [119,120]. E maintains and inhibits SOST expression through ERα and ERβ, respectively [123]. A favors the expression of SOST through ARs [118]. Sclerostin, the protein encoded by SOST, acts as a negative feedback mechanism on the Wnt pathway. Sclerostin increases osteoclast differentiation by increasing RANKL expression [121]. FasL signaling pathway (d): E induces transcription of FasL via ERα activation [125,126], and the soluble FasL stimulates osteoclast apoptosis [124,125]. E regulates anti-apoptotic protein Bcl2 in osteoblasts [128]. E also induces the transcription of the ALPL gene via ERα to promote bone mineralization [13,130]. IGF signaling pathway (e): A and AR signaling increase expression of IGFBP3. A also induces the expression of IGF and ALPL; ALPL could promote osteogenesis [135]. IGF-I activates MAPK signaling, ultimately leading to osteoclast differentiation [131]. IGF-I and E also activate PI3K, upregulating Akt, which promotes mTOR gene expression and osteoblast formation [132]. PTH, CT, and VitD signaling pathway (f): A low blood Ca²⁺ level activates the PTH signaling pathway. PTH1R is implicated in the activation of AC-PKA and PLC-PKC signaling pathway [136,137]. Activation of the cAMP/PKA signaling pathway results in promotion of bone formation or bone resorption [80,[138], [139], [140], [141]]. PLC activates PKC and IP3 production, subsequently activating calcium mobilization and increasing blood Ca²⁺ level [145]. E and A suppresses PTH-stimulated osteoclast-like cell formation by blocking both the AC-PKA and PLC-PKC signaling pathways [146,147]. PTH increases 1α(OH)ase synthesis, which promotes 1,25(OH)₂D₃ synthesis, in turn suppressing PTH production. 1,25(OH)₂D₃ acting via the VDR mediates negative or positive effects in bone [151]. A high blood Ca²⁺ level activates the calcitonin (CT) signaling pathway. The physiological effects of CT to decrease circulating Ca²⁺ levels through the inhibition of bone resorption are mediated by CT receptors (CTRs) [159]. E could increase CT secretory capacity [163].